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Inflammasomes and human autoimmunity: A comprehensive review
Abstract
Inflammasomes are multi-protein complexes composed of a NOD-like receptor (NLR)/an AIM-like receptor (ALR), the adapter molecule apoptosis-associated speck-like protein that contains a CARD (ASC), and caspase-1. Active caspase-1 cleaves pro-IL-1β and pro-IL-18 to IL-1β and IL-18, resulting in inflammation. Genetic mutations in inflammasomes were first recognized to result in autoinflammatory diseases, which are characterized by the absence of both autoantibodies and autoreactive-T/B cells. However, there is increasing attention being placed on genetic polymorphisms that are involved in the components of inflammasomes, and these have implications for innate immunity and the natural history of autoimmune diseases. For example, while the NOD-like receptor family, pyrin domain containing 1 (NLRP1) haplotypes contributes to susceptibility to developing vitiligo; there are other single nucleotide polymorphisms (SNPs) that alters the susceptibility and severity of rheumatoid arthritis (RA) and juvenile idiopathic arthritis. Indeed, there are multiple factors that contribute to lowering the threshold of immunity and inflammasomes play a key role in this threshold. For example, IL-1β and IL-18 further perpetuate Th17 responses and endothelial cell damage, which potentiate a number of autoimmune diseases, including synovitis in RA, cardiovascular disease, and systemic lupus erythematosus (SLE). There is also increasing data on the role of innate immunity in experimental autoimmune encephalomyelitis (EAE), in lupus nephritis, and in a variety of autoimmune pathologies in which activation of the innate immune system is the driver for the adaptive system. Indeed, it is likely that the chronic pathology of autoimmunity is mediated in part by otherwise innocent bystander cells, augmented by inflammasomes.
Copyright © 2015 Elsevier Ltd. All rights reserved.
... Activated NLRP3 interacts with an adaptor protein, ASC, that bridges it to pro-Caspase-1 forming a multi-protein complex called inflammasome (2)(3)(4)(5)(6)(7)(8). Dysregulation of NLRP3 inflammasome activity is a hallmark of pathogenesis in several human diseases (20)(21)(22)(23)(24), indicating its highly significant clinical relevance. In this review, we summarize the existing knowledge about the mechanism of activation of NLRP3 and its regulation during activation by infectious and sterile triggers (Figure 1). ...
... Several host factors are also involved in the activation of the NLRP3 inflammasome during bacterial infections. For example, IRF8 promotes Ifnb transcription which in turn activates caspase-11 to trigger the NLRP3 inflammasome in murine macrophages infected with Citrobacter rodentium (24). In another study, TRIF was identified as an important bridge between TLR4 and NLRP3 in enterohemorrhagic Escherichia coli (EHEC) and C. rodentium infected cells (25). ...
Nod-Like Receptor (NLR) is the largest family of Pathogen Recognition Receptors (PRRs) that patrols the cytosolic environment. NLR engagement drives caspase-1 activation that cleaves pro-IL-1B which then gets secreted. Released IL-1B recruits immune cells to the site of infection/injury. Caspase-1 also cleaves Gasdermin-D (GSDM-D) that forms pores within the plasma membrane driving inflammatory cell death called pyroptosis. NLRP3 is the most extensively studied NLR. The NLRP3 gene is encoded by 9 exons, where exon 1 codes for pyrin domain, exon 3 codes for NACHT domain, and Leucine Rich Repeat (LRR) domain is coded by exon 4-9. Exon 2 codes for a highly disorganized loop that connects the rest of the protein to the pyrin domain and may be involved in NLRP3 regulation. The NLRP3 inflammasome is activated by many structurally divergent agonists of microbial, environmental, and host origin. Activated NLRP3 interacts with an adaptor protein, ASC, that bridges it to pro-Caspase-1 forming a multi-protein complex called inflammasome. Dysregulation of NLRP3 inflammasome activity is a hallmark of pathogenesis in several human diseases, indicating its highly significant clinical relevance. In this review, we summarize the existing knowledge about the mechanism of activation of NLRP3 and its regulation during activation by infectious and sterile triggers.
... Previously, it has been shown that the function of the NLRP3 inflammasome produces and activates proinflammatory cytokines such as interleukin (IL)-1β and IL-18 [11]. However, recent studies have described that inflammasome is transcribed in an imbalance in cytoplasmic homeostasis and molecular patterns [12,13], thus the inflammasome is implicated in various inflammatory diseases, such as peritonitis, gouty arthritis, and type 2 diabetes as well as cancers [14][15][16][17][18]. These evidences suggest that NLRP3 inflammasome contributes to the development of various diseases. ...
... The NLRP3 inflammasome which is one of inflammasomes well-studied has been known to activate pro-inflammatory cytokines, such as IL-1β. However, emerging evidences indicate that the function of NLRP3 inflammasome is associated with many diseases including tumorigenesis [17], autoimmune disorders [14,15], and neurodegenerative diseases [17,18]. According to recent reports, NLRP3 inflammasome is influenced by molecular patterns which caused by an imbalance of cytoplasmic homeostasis [12,13], thus that might be related to cancer development. ...
Human hepatocellular carcinoma (HCC) is the most common and even worse at prognosis. The patients with HCC which accompanied by other diseases, such as cirrhosis, can be limited in various treatments, such as chemotherapy, not HCC patients without other diseases. NLRP3 inflammasome plays an important role in the innate immune response, but emerging evidence has indicated that the NLRP3 inflammasome is implicated in all stages of cancer development. Various cells express NLRP3 protein through the autocrine or paracrine signaling in their environment, but NK cells do not. The expanding evidence shows that patients who suffer from liver cancers have a low frequency of natural killer (NK) cells, and the function of these cells is also impaired. Thus, we examined how the expression of NLRP3 in HCC cells affects cancer surveillance by NK cells in a state of a co-culture of both cells. When the expression of NLRP3 in HCC cells was ablated, MICA/B on the surface of HCC cells was upregulated through the lowered expression of matrix metalloproteinase. The expression of MICA on the surface of HCC cells interacted with the NKG2D receptor on NK-92 cells, which led to NK cytotoxicity. Furthermore, in a xenograft mice model, NLRP3 KO HCC cells delayed tumor development and metastasis as well as increased the sensitivity to NK cell cytotoxicity. Taken together, NLRP3 KO in HCC could enhance NK immunosurveillance through an interaction of NKG2D-MICA.
... Dysregulated interactions between genes and environment have been suggested to result in human autoimmune diseases [1]. Inflammasomes are multi-protein complexes which play important roles in sensing pathogens and cellular perturbations, including pathogen-associated molecular patterns (PAMPs), danger-associated molecular patterns (DAMPs), and homeostasis-altering molecular processes (HAMPs) [2,3]. Upon sensing of these molecular patterns/ processes, the inflammasome complexes assemble and function to cleave the inactive IL-1 family cytokine precursors and Gasdermin D (GSDMD). ...
... Genetic variants in components of NOD-like receptor (NLR)-associated inflammasomes, such as NLRP1 and NLRP3, have been reported to be associated with susceptibility to autoimmune diseases in adults [2]. In children, mutations in inflammasome components are wellknown causes of monogenic autoinflammatory diseases, including familial Mediterranean fever (FMF) and cryopyrin-associated periodic syndromes (CAPS). ...
Inflammasomes are multiprotein complexes capable of sensing pathogen-associated molecular patterns (PAMPs), danger-associated molecular patterns (DAMPs), and cellular perturbations. Upon stimulation, the inflammasomes activate the production of the pro-inflammatory cytokines IL-1β and IL-18 and induce gasdermin D-mediated pyroptosis. Dysregulated inflammasome signaling could lead to hyperinflammation in response to environmental triggers, thus contributing to the pathogenesis of childhood autoimmune/autoinflammatory diseases. In this review, we group childhood rheumatic diseases into the autoinflammation to autoimmunity spectrum and discuss about the involvement of inflammasomes in disease mechanisms. Genetic mutations in inflammasome components cause monogenic autoinflammatory diseases, while inflammasome-related genetic variants have been implicated in polygenic childhood rheumatic diseases. We highlight the reported associations of inflammasome signaling-related genetic polymorphisms/protein levels with pediatric autoimmune disease susceptibility and disease course. Furthermore, we discuss about the use of IL-1 receptor antagonist as an adjunctive therapy in several childhood autoimmune diseases, including macrophage activation syndrome (MAS) and multisystem inflammatory syndrome in children (MIS-C) related to COVID-19. A comprehensive multi-cohort comparison on inflammasome gene expression profile in different pediatric rheumatic diseases is needed to identify patient subsets that might benefit from the adjunctive therapy of IL-1β inhibitors.
... However, the NLRP3 inflammasome is activated by structurally and chemically diverse triggers of human, microbial, and environmental origin (12,13,15,(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37). Further, activating mutations in the NLRP3 gene mediate hereditary autoinflammatory diseases ranging in severity from the mild familial cold autoinflammatory syndrome (FCAS) to the severe neonatal-onset multisystem inflammatory disease (NOMID) (38)(39)(40)(41)(42)(43)(44)(45)(46)(47). Moreover, dysregulated NLRP3 inflammasome responses are a contributing factor in various inflammatory and autoimmune diseases (41-43, 46, 47). ...
... Expression plasmids encoding human NLRP1, NLRP2, caspase-1, and pro-IL-1β were all obtained from Open BioSystems. Human FLAG-NLRP3, and myc-ASC have been described previously (47). All restriction enzymes were obtained from New England Biolabs. ...
The NLRP3 inflammasome is central to host defense and implicated in various inflammatory diseases and conditions. While the favored paradigm of NLRP3 inflammasome activation stipulates a unifying signal intermediate that de-represses NLRP3, this view has not been tested. Further, structures within NLRP3 required for inflammasome activation are poorly defined. Here we demonstrate that while the NLRP3 LRRs are not auto-repressive and are not required for inflammasome activation by all agonists, distinct sequences within the NLRP3 LRRs positively and negatively modulate inflammasome activation by specific ligands. In addition, elements within the HD1/HD2 “hinge” of NLRP3 and the nucleotide-binding domain have contrasting functions depending upon the specific agonists. Further, while NLRP3 1–432 is minimally sufficient for inflammasome activation by all agonists tested, the pyrin, and linker domains (1–134) function cooperatively and are sufficient for inflammasome activation by certain agonists. Conserved cysteines 8 and 108 appear important for inflammasome activation by sterile, but not infectious insults. Our results define common and agonist-specific regions of NLRP3 that likely mediate ligand-specific responses, discount the hypothesis that NLRP3 inflammasome activation has a unified mechanism, and implicate NLRP3 as an integrator of agonist-specific, inflammasome activating signals.
... Due to the lack of digestibility in the earlier parts of the gastrointestinal tract, carrageenan directly interacts with the gut microbiota and can be utilized by gut microorganisms. Studies have demonstrated alterations in the composition of the gut microbiome, resulting in a reduction in the thickness of the intestinal barrier and mucin content [24]. Mucin is a glycoprotein that forms the intestinal mucus layer [44]. ...
Carrageenan is a widely used food additive and is seen as a potential candidate in the pharmaceutical industry. However, there are two faces to carrageenan that allows it to be used positively for therapeutic purposes. Carrageenan can be used to create edible films and for encapsulating drugs, and there is also interest in the use of carrageenan for food printing. Carrageenan is a naturally occurring polysaccharide gum. Depending on the type of carrageenan, it is used in regulating the composition of intestinal microflora, including the increase in the population of Bifidobacterium bacteria. On the other hand, the studies have demonstrated the harmfulness of carrageenan in animal and human models, indicating a direct link between diet and intestinal inflammatory states. Carrageenan changes the intestinal microflora, especially Akkermansia muciniphilia, degrades the mucous barrier and breaks down the mucous barrier, causing an inflammatory reaction. It directly affects epithelial cells by activating the pro-inflammatory nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) pathway. The mechanism is based on activation of the TLR4 receptor, alterations in macrophage activity, production of proinflammatory cytokines and activation of innate immune pathways. Carrageenan increases the content of Bacteroidetes bacteria, also causing a reduction in the number of short chain fatty acid (SCFA)-producing bacteria. The result is damage to the integrity of the intestinal membrane and reduction of the mucin layer. The group most exposed to the harmful effects of carrageenan are people suffering from intestinal inflammation, including Crohn disease (CD) and ulcerative colitis (UC).
... All subjects of the study were genotyped by TaqMan assays for the following single nucleotide polymorphisms (SNPs), which are located in the genes involved in the formation and signaling of the inflammasome that have previously been associated with the susceptibility and development of various immune and inflammatory diseases [34][35][36][37][38][39][40][41]: NLRP3 (rs4925659, rs10159239, rs10754558, and rs4353135); NLRC4 (rs385076 and rs479333); NLRP1 (rs4790797, rs8182352, rs878329, rs2670660, rs12150220, and rs6502867); CARD8 (rs11672725, rs6509365, and rs2043211); CASP1 (rs501192 and rs488992); IL1B (rs1143634 and rs16944); IL18 (rs187238); NFKB1 (rs28362491); ATG16L1 (rs2241880 and rs6754677); and MIF (rs755622). Negative controls and duplicate samples were included to check the accuracy of the genotyping. ...
The most critical forms of coronavirus disease 2019 (COVID-19) are associated with excessive activation of the inflammasome. Despite the COVID-19 impact on public health, we still do not fully understand the mechanisms by which the inflammatory response influences disease prognosis. Accordingly, we aimed to elucidate the role of polymorphisms in the key genes of the formation and signaling of the inflammasome as biomarkers of COVID-19 severity. For this purpose, a large and well-defined cohort of 377 COVID-19 patients with mild (n = 72), moderate (n = 84), severe (n = 100), and critical (n = 121) infections were included. A total of 24 polymorphisms located in inflammasome-related genes (NLRP3, NLRC4, NLRP1, CARD8, CASP1, IL1B, IL18, NFKB1, ATG16L1, and MIF) were genotyped in all of the patients and in the 192 healthy controls (HCs) (who were without COVID-19 at the time of and before the study) by RT-qPCR. Our results showed that patients with mild, moderate, severe, and critical COVID-19 presented similar allelic and genotypic distribution in all the variants studied. No statistically significant differences in the haplotypic distribution of NLRP3, NLRC4, NLRP1, CARD8, CASP1, IL1B, and ATG16L1 were observed between COVID-19 patients, who were stratified by disease severity. Each stratified group of patients presented a similar genetic distribution to the HCs. In conclusion, our results suggest that the inflammasome polymorphisms studied are not associated with the worsening of COVID-19.
... In recent years, many scholars have reported on the role of leukocyte telomeres in atherosclerosis [5][6][7], and novel indices such as the systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), and comprehensive systemic inflammation index (AISI) have been derived to serve as objective markers for assessing the balance between host systemic inflammation and immune response. These indices have been shown to have predictive value for the prognosis of cardiovascular diseases [8][9][10][11][12][13][14][15]. Some studies have revealed other parameters calculated by combining different biochemical indicators or individual biochemical indicators. ...
Objective
The aim of this study was to investigate the association between quantitative coronary flow reserve (CFR) and the blood uric acid/albumin ratio, as well as multiple clinical parameters, in order to assess the severity of coronary artery functional stenosis.
Methods
This retrospective cross-sectional study included 257 suspected coronary artery disease patients who underwent coronary angiography (CAG) and quantitative flow ratio (QFR) examinations in the Department of Cardiovascular Medicine at the First Affiliated Hospital of Yangtze University in Jingzhou City, China, between September 2022 and March 2023. The study subjects were divided into two groups based on their QFR values: QFR ≤ 0.80 group and QFR > 0.80 group. Correlation of uric acid-to-albumin ratio (UAR), high-density lipoprotein ratio (MHR), systemic immune-inflammation index (SII), Systemic Inflammation Response Index (SIRI), and Aggregate Index of Systemic Inflammation (AISI) with coronary artery QFR was analyzed using univariate and multivariate logistic regression models, considering them as both continuous and binary variables.
Results
The QFR ≤ 0.80 group consisted of 83 patients, while the QFR > 0.80 group included 174 patients. Significant differences were observed between the QFR ≤ 0.80 and QFR > 0.80 groups in the following parameters: UAR (9.19 ± 2.47 vs 7.61 ± 1.91; p < 0.001), MHR (0.46 ± 0.19 vs 0.37 ± 0.16, p < 0.001), SII (674.98 ± 332.30 vs 571.43 ± 255.82; p = 0.006), SIRI (1.53 ± 0.83 vs 1.29 ± 1.10; p = 0.047), and AISI (340.22 ± 242.10 vs 243.97 ± 151.97; p < 0.001). ROC curve analysis revealed an area under the curve of 0.701 (CI: 0.633–0.770; p < 0.001) for UAR. In the univariate analysis, when treated as binary variables, high levels of UAR, MHR, SII, SIRI, and AISI were found to be significantly associated with the risk of QFR ≤ 0.80 (all P < 0.05). However, in the multivariate regression analysis, only high levels of UAR and AISI remained significantly associated with QFR ≤ 0.80 (all P < 0.05). When treated as continuous variables, the univariate analysis indicated that UAR (OR: 1.412, CI: 1.231–1.620, p < 0.001), e^MHR (OR: 1.394, CI: 1.151–1.687, p < 0.001), lnSII (OR: 1.001, CI: 1.000–1.002, p = 0.008), and lnAISI (OR: 2.695, CI: 1.539–4.719, p = 0.001) were significantly associated with QFR ≤ 0.80. In the multivariate analysis, UAR (OR: 1.373, CI: 1.187–1.587, p < 0.001) and AISI (OR: 2.217, CI: 1.309–3.757, p < 0.001) remained significantly associated with QFR ≤ 0.80.
Conclusions
The results of this study indicate a significant association between UAR and AISI with QFR ≤ 0.80, suggesting its potential role in predicting the extent of functional coronary artery stenosis in patients with CAD. Additionally, AIRI, identified as an inflammatory marker in the complete blood count, was found to exert influence on the severity of coronary artery physiology.
... IL-17 signaling pathway was enriched in the KEGG pathway enrichment. 38 IL-1β, with the help of IL-23, promotes the production of innate IL-17 from γδ T cells, which further contributes to the generation of Th17 cells. 39 The pathogenic Th17 cells contribute to the secretion of IFN-γ and then add to the IFN-γ-mediated inflammatory disease. ...
Background
Vitiligo and Hashimoto’s thyroiditis (HT) are concomitant autoimmune diseases characterized by the destruction of melanocytes or thyrocytes. We aimed to explore the immunological mechanism of this comorbidity and screen their potential biomarkers.
Methods
We downloaded the microarray datasets from the GEO database. Differentially expressed genes (DEGs) and immune-related genes (IRGs) were selected. The immune-related differentially expressed genes (IRDEGs) were obtained by taking the intersection. Candidate biomarkers were elected by Cytoscape software. CIBERSORT was used to depict immune cell infiltration prospects. Correlation analysis was conducted between infiltrating cells and several indicators. The results were validated by real-time quantitative PCR (RT-qPCR).
Results
Three datasets and 60 IRDEGs were obtained in total. Pathway enrichment analysis showed that the T cell receptor signaling pathway, IL-17 signaling pathway, receptor-ligand activity, and signaling receptor activator activity were significantly enriched. We screened out four hub genes, including IFNG, STAT1, IL1B, and CXCL10. The ROC curve indicated the highest diagnostic value of CXCL10 in both vitiligo and HT. Immuno-infiltration analysis revealed significant changes in T cell subsets and macrophage subtypes, which were correlated with four hub genes, melanocyte markers, and thyroid-specific antigens. qPCR validated the hub genes in peripheral blood mononuclear cells from patients with comorbidity.
Conclusion
IFNG, STAT1, IL1B, and CXCL10, were the key IRDEGs to vitiligo and HT. These genes may participate in the comorbidity by remodeling the immune cell infiltration pattern, and cross-expressed antigens may mediate the common damage of melanocytes and thyroid tissues.
... Given its pleiotropic function in shaping the activity of the immune system, P2X7R has been implicated in the pathogenesis and progression of autoimmunity; however, its contribution remains controversial since both beneficial and detrimental effects have been observed. Certainly, its role in inflammation and innate immunity is relevant in many autoimmune diseases, as P2X7R-mediated secretion of proinflammatory cytokines, chemokines, and other soluble mediators can fuel the autoimmune reaction [58]. Therefore, exploiting P2X7R as a potential therapeutic target could represent a promising opportunity to ameliorate the pathological manifestations suffered by many patients affected by inflammatory and autoimmune disorders. ...
The P2X7 receptor (P2X7R) is an ATP-gated nonselective cationic channel that, upon intense stimulation, can progress to the opening of a pore permeable to molecules up to 900 Da. Apart from its broad expression in cells of the innate and adaptive immune systems, it is expressed in multiple cell types in different tissues. The dual gating property of P2X7R is instrumental in determining cellular responses, which depend on the expression level of the receptor, timing of stimulation, and microenvironmental cues, thus often complicating the interpretation of experimental data in comprehensive settings. Here we review the existing literature on P2X7R activity in autoimmunity, pinpointing the different functions in cells involved in the immunopathological processes that can make it difficult to model as a druggable target.
... Previous studies have shown that caspase-1 also cleaves GSDMD to promote the release of IL-1β and IL-18 and that non-canonical inflammasomes activate the canonical NLRP3 inflammasome [25,31]. Inflammasome dysregulation has been shown to be associated with tumor development, autoimmune diseases and neurodegenerative diseases [33][34][35]. The most studied NLRP3 inflammasome is known to induce angiogenesis and confer a mesenchymal phenotype by upregulating the production of IL-1β in GBM [36]. ...
Background:
Inflammasomes are key in the initiation of inflammatory responses and serve to defend the organism. However, when the immune system is imbalanced, these complexes contribute to tumor progression. The purpose of this study was to investigate the effect of non-canonical inflammasomes on glioma malignancy.
Methods:
We performed bioinformatics analysis to confirm the expression of canonical and non-canonical inflammasome-related molecules according to the degree of malignancy through immunohistochemical examination of glioma tissues obtained with patient consent from our institution.
Results:
Bioinformatics analysis confirmed that the expression levels of non-canonical inflammasome-related molecules were significantly higher in tumor tissues than in normal tissues, and they also increased according to malignancy, which adversely affected the survival rate. Furthermore, in gliomas, positive correlations were found between N-form gasdermin-D, a key molecule associated with the non-canonical inflammasome, and other related molecules, including NLRP3, caspase-1, caspase-4, and caspase-5. These results were verified by immunohistochemical examination of glioma tissues, and the expression levels of these molecules also increased significantly with increasing grade. In addition, the features of pyroptosis were confirmed.
Conclusion:
This study identified the potential of non-canonical inflammasomes as aggressiveness markers for gliomas and presented a perspective for improving glioma treatment.
... Our results showed that co-crossover genes were significantly enriched in IL-17 signaling pathway, Th17 cell differentiation signaling, nod-like receptor signaling pathway, and these signaling pathways, which have been shown to be involved in mediating immune regulation in vitiligo [44][45][46] . These results are consistent with a recent Figure 6. ...
Coronavirus disease 2019 (COVID-19) is spreading rapidly around the world. However, the treatment of vitiligo combined with COVID-19 has not been reported. Astragalus membranaceus (AM) has a therapeutic effect on patients with vitiligo and COVID-19. This study aims to discover its possible therapeutic mechanisms and provide potential drug targets. Using the Chinese Medicine System Pharmacological Database (TCMSP), GEO database and Genecards websites and other databases, AM target, vitiligo disease target, and COVID-19 related gene set were established. Then find the crossover genes by taking the intersection. Then use GO, KEGG enrichment analysis, and PPI network to discover its underlying mechanism. Finally, by importing drugs, active ingredients, crossover genes, and enriched signal pathways into Cytoscape software, a “drug-active ingredient-target signal pathway-” network is constructed. TCMSP screened and obtained 33 active ingredients including baicalein (MOL002714), NEOBAICALEIN (MOL002934), Skullcapflavone II (MOL002927), and wogonin (MOL000173), which acted on 448 potential targets. 1166 differentially expressed genes for vitiligo were screened by GEO. CIVID-19 related genes were screened by Genecards. Then by taking the intersection, a total of 10 crossover genes (PTGS2, CDK1, STAT1, BCL2L1, SCARB1, HIF1A, NAE1, PLA2G4A, HSP90AA1, and HSP90B1) were obtained. KEGG analysis found that it was mainly enriched in signaling pathways such as IL-17 signaling pathway, Th17 cell differentiation, Necroptosis, NOD-like receptor signaling pathway. Five core targets (PTGS2, STAT1, BCL2L1, HIF1A, and HSP90AA1) were obtained by analyzing the PPI network. The network of "active ingredients-crossover genes" was constructed by Cytoscape, and the 5 main active ingredients acting on the 5 core crossover genes acacetin, wogonin, baicalein, bis2S)-2-ethylhexyl) benzene-1,2-dicarboxylate and 5,2′-Dihydroxy-6,7,8-trimethoxyflavone. The core crossover genes obtained by PPI and the core crossover genes obtained by the "active ingredient-crossover gene" network are intersected to obtain the three most important core genes (PTGS2, STAT1, HSP90AA1). AM may act on PTGS2, STAT1, HSP90AA1, etc. through active components such as acacetin, wogonin, baicalein, bis2S)-2-ethylhexyl) benzene-1,2-dicarboxylate and 5,2′-Dihydroxy-6,7,8-trimethoxyflavone to activate IL-17 signaling pathway, Th17 cell differentiation, Necroptosis, NOD-like receptor signaling pathway, Kaposi sarcoma-associated herpesvirus infection, and VEGF signaling pathway and other signaling pathways to achieve the effect of treating vitiligo and COVID-19.
... Both pDCs and NLRP3 receptor overexpression play a role in the pathogenesis and pathomechanism of various autoimmune diseases. Numerous single nucleotide polymorphisms (SNPs) of NLRP3, which are mainly gain-of-function mutations, have been described, for example, in SLE, IBD, MS, RA and psoriasis [139,140]. In addition, pDCs may also play a role in the pathogenesis of psoriasis, since self-nucleic acids released by dying cells in complex with overproduced LL37 cationic antimicrobial peptides induce the persistent activation and excessive type I IFN production of pDCs, which promotes the development of T cell-mediated autoimmune responses [141,142]. ...
Generally, a reciprocal antagonistic interaction exists between the antiviral type I interferon (IFN) and the antibacterial nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain containing 3 (NLRP3)-dependent IL-1β pathways that can significantly shape immune responses. Plasmacytoid dendritic cells (pDCs), as professional type I IFN-producing cells, are the major coordinators of antiviral immunity; however, their NLRP3-dependent IL-1β secretory pathway is poorly studied. Our aim was to determine the functional activity of the IL-1β pathway and its possible interaction with the type I IFN pathway in pDCs. We found that potent nuclear factor-kappa B (NF-κB) inducers promote higher levels of pro-IL-1β during priming compared to those activation signals, which mainly trigger interferon regulatory factor (IRF)-mediated type I IFN production. The generation of cleaved IL-1β requires certain secondary signals in pDCs and IFN-α or type I IFN-inducing viruses inhibit IL-1β production of pDCs, presumably by promoting the expression of various NLRP3 pathway inhibitors. In line with that, we detected significantly lower IL-1β production in pDCs of psoriasis patients with elevated IFN-α levels. Collectively, our results show that the NLRP3-dependent IL-1β secretory pathway is inducible in pDCs; however, it may only prevail under inflammatory conditions, in which the type I IFN pathway is not dominant.
... High mRNA expression of GSDMD and IL-1β in PBMCs from SLE patients Previous studies have shown that activated inflammasomes are closely related to the severity of the disease in SLE patients [25,[34][35][36], suggesting that GSDMD-mediated pyroptosis might be involved in SLE. We first determined the expression of GSDMD gene in PBMCs from SLE patients and healthy controls by real-time PCR analysis. ...
Activation of multiple inflammasomes in monocytes/macrophages is associated with the pathogenesis of systemic lupus erythematosus (SLE). Gasdermin D (GSDMD)-mediated pyroptosis, a common consequence of multiple activated inflammasomes, is a programmed cell death with strong inflammatory responses. This suggested that targeting monocyte/macrophage pyroptosis might provide an opportunity to cure SLE. Here, we aimed to investigate the effect of disulfiram (DSF), a small molecule inhibitor of pyroptosis, and its potential therapeutic mechanism for SLE. The mRNA expression of GSDMD and IL-1β were significantly increased in peripheral blood mononuclear cells (PBMCs) from SLE patients. Importantly, we found serum from SLE patients rather than healthy controls induced GSDMD-mediated pyroptosis in THP-1 cells, as evidenced by enhanced LDH release, increased number of PI-positive cells, and high expression of full-length GSDMD and N-terminal GSDMD. Interestingly, treatment with DSF obviously inhibited pyroptosis of THP-1 cells induced by serum from SLE patients. Of note, DSF administration reduced proteinuria, serum anti-dsDNA level, and renal immune complex. It also attenuated renal damage in PIL mice. Further research found that the high level of serum IL-β and GSDMD-mediated pyroptosis of glomerular macrophages in PIL mice were rescued with DSF treatment. These data implied that GSDMD-mediated monocytes/macrophages pyroptosis played an important role in the pathogenesis of SLE and DSF might be a potential alternative therapeutic agent for SLE.
... Mutations in NLRP3 are the prototypic inflammasomopathy, but they have also been described as autoinflammatory diseases associated with mutations that activate the NLRP1, NLRC4 and pyrin inflammasomes [69,70]. Moreover, single nucleotide polymorphisms (SNPs) play a crucial role in autoimmune diseases, and they can affect the priming of inflammasomes, some of their components or end products (IL-1β, IL-18) [71]. ...
The inflammasome is an immune multiprotein complex that activates pro-caspase 1 in response to inflammation-inducing stimuli and it leads to IL-1β and IL-18 proinflammatory cytokine production. NLRP1 and NLRP3 inflammasomes are the best characterized and they have been related to several autoimmune diseases. It is well known that the kidney expresses inflammasome genes, which can influence the development of some glomerulonephritis, such as lupus nephritis, ANCA glomerulonephritis, IgA nephropathy and anti-GBM nephropathy. Polymorphisms of these genes have also been described to play a role in autoimmune and kidney diseases. In this review, we describe the main characteristics, activation mechanisms, regulation and functions of the different inflammasomes. Moreover, we discuss the latest findings about the role of the inflammasome in several glomerulonephritis from three different points of view: in vitro, animal and human studies.
... IL-18 is one of the factors most related to autoimmunity [45][46][47][48] due to its potent and complex pro-inflammatory action. IL-18 is also known to play a key role in melanoma regulation [49] and is one of the AIM2 inflammasome components [50], recently recognized as a potential target for melanoma treatment [51]. ...
Simple Summary
The present study selected four genes strongly related to autoimmunity. Their expression was found to be significantly altered in melanoma patients according to a multi-validation procedure carried out on 1948 patients. Such genes may represent suitable molecular targets to further investigate the role autoimmunity may play in melanoma setup and development. Our data suggest that autoimmunity may play a beneficial role in melanoma set up, at least to some extent.
Abstract
(1) Background. Immune response dysregulation plays a key role in melanoma, as suggested by the substantial prognosis improvement observed under immune-modulation therapy. Similarly, the role of autoimmunity is under large investigation in melanoma and other cancers. (2) Methods. Expression of 98 autoimmunity-related genes was investigated in 1948 individuals (1024 melanoma and 924 healthy controls). Data were derived from four independent databases, namely, GEO in the selection phase, and Ist Online, GEPIA2 and GENT2, in three sequential validation-steps. ROC analyses were performed to measure the ability to discriminate melanoma from controls. Principal Component Analysis (PCA) was used to combine expression data; survival analysis was carried out on the GEPIA2 platform. (3) Results. Expression levels of NOD2, BAX, IL-18 and ADRB2 were found to be significantly different in melanoma vs. controls and discriminate melanoma from controls in an extremely effective way, either as single molecules (AUC > 0.93 in all cases) or as a profile, according to the PCA analysis. Patients showing high-expression of NOD2 and of IL-18 also show a significant survival improvement as compared to low-expression patients. (4) Conclusions. Four genes strongly related to autoimmunity show a significant altered expression in melanoma samples, highlighting the role they may play in melanoma.
... On the other hand, Yang and coworkers attempted to summarize the role of inflammasomes on innate immunity and the natural history of autoimmune diseases. They showed that inflammasomes play a key role in lowering the threshold of immunity, thereby potentiating a number of autoimmune diseases (209). Si Ming Man et al. elaborated on the role of AIM2 inflammasomes in cancer and autoimmunity, that inappropriate recognition of cytoplasmic self-DNA by AIM2 contributes to the development of psoriasis, dermatitis, arthritis, and other autoimmune and/or inflammatory diseases (210). ...
Radiation-induced lung injury (RILI) is a form of radiation damage to normal lung tissue caused by radiotherapy (RT) for thoracic cancers, which is most commonly comprised of radiation pneumonitis (RP) and radiation pulmonary fibrosis (RPF). Moreover, with the widespread utilization of immunotherapies such as immune checkpoint inhibitors as first- and second-line treatments for various cancers, the incidence of immunotherapy-related lung injury (IRLI), a severe immune-related adverse event (irAE), has rapidly increased. To date, we know relatively little about the underlying mechanisms and signaling pathways of these complications. A better understanding of the signaling pathways may facilitate the prevention of lung injury and exploration of potential therapeutic targets. Therefore, this review provides an overview of the signaling pathways of RILI and IRLI and focuses on their crosstalk in diverse signaling pathways as well as on possible mechanisms of adverse events resulting from combined radiotherapy and immunotherapy. Furthermore, this review proposes potential therapeutic targets and avenues of further research based on signaling pathways. Many new studies on pyroptosis have renewed appreciation for the value and importance of pyroptosis in lung injury. Therefore, the authors posit that pyroptosis may be the common downstream pathway of RILI and IRLI; discussion is also conducted regarding further perspectives on pyroptosis as a crucial signaling pathway in lung injury treatment.
... Hereditary diseases of inflammasomes cause autoimmune and autoinflammatory disorders such as rheumatoid arthritis, systemic lupus erythematosus, cryopyrin-associated autoinflammatory disease, and pyoderma gangrenosum [37,38]. The spectrum of autoinflammatory diseases linked to the inflammasome has expanded rapidly over the last decade [39]. ...
The nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein (NLRP) inflammasome is a key inflammatory signaling pathway activated via a two-step signaling process consisting of priming and activation steps. Several studies have shown that 1,25-dihydroxyvitamin D3 (1,25(OH)2VD3) inhibits the priming step required for NLRP3 inflammasome activation in immune cells. However, as activating the NLRP1 inflammasome in keratinocytes does not necessarily require a priming step, whether 1,25(OH)2VD3 inhibits NLRP1 activation in unprimed keratinocytes is currently unknown. In this study, we showed that 1,25(OH)2VD3 inhibits nigericin-induced NLRP1 inflammasome activation in unprimed keratinocytes. 1,25(OH)2VD3 suppressed nigericin-induced interleukin-1β (IL-1β) secretion and caspase-1 activation in human primary keratinocytes. In addition, 1,25(OH)2VD3 significantly inhibited the formation of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) oligomers and specks, but not caspase-1 enzymatic activity, suggesting that 1,25(OH)2VD3 prevents NLRP1-ASC complex assembly in keratinocytes. Vitamin D receptor (VDR)-knockdown abolished the inhibitory effects of 1,25(OH)2VD3 on nigericin-induced ASC oligomerization and IL-1β secretion, suggesting that 1,25(OH)2VD3 suppresses inflammasome activation via VDR signaling. Furthermore, nigericin induced K⁺ efflux and cellular reactive oxygen species (ROS) production, and 1,25(OH)2VD3 pretreatment suppressed nigericin-induced ROS production. 1,25(OH)2VD3 increased the expression of both nuclear factor erythroid 2-related factor 2 (NRF2) and heme oxygenase-1 (HO-1), whereas HO-1 inhibition or NRF2 and HO-1 knockdown abrogated the inhibitory effects of 1,25(OH)2VD3 on IL-1β secretion. Our results indicate that 1,25(OH)2VD3 inhibits nigericin-induced activation step of NLRP1 inflammasome activation in unprimed keratinocytes. Our findings reveal the mechanism underlying the inhibitory effect of 1,25(OH)2VD3, which involves NRF2-HO-1 pathway activation through the VDR, providing further insight into the potential function of 1,25(OH)2VD3 as a therapeutic agent for inflammasome-related skin diseases.
... Although some autoimmune diseases are monogenic, the majority are polygenic by nature (Doria et al., 2012). Genetic polymorphisms leading to increased expression and activation of inflammasome proteins (e.g., NLRP3), TLRs (e.g., TLR7, TLR9), transcription factors (e.g., STAT4), and IFN signaling proteins (e.g., IRF5) have been associated with increased susceptibility and severity of several autoimmune diseases including SLE, rheumatoid arthritis (RA), and multiple sclerosis (Cho and Gregersen, 2011;Yang and Chiang, 2015). In addition, loss-of-function mutations in efferocytosis receptors (e.g., MerTK), which leads to decreased engulfment of cytotoxic cell debris, have been associated with systemic autoimmunity (Lemke, 2013). ...
Exposure to exogenous particles found as airborne contaminants or endogenous particles that form by crystallization of certain nutrients can activate inflammatory pathways and potentially accelerate autoimmunity onset and progression in genetically predisposed individuals. The first line of innate immunological defense against particles are myeloid-lineage phagocytes, namely macrophages and neutrophils, which recognize/internalize the particles, release inflammatory mediators, undergo programmed/unprogrammed death, and recruit/activate other leukocytes to clear the particles and resolve inflammation. However, immunogenic cell death and release of damage-associated molecules, collectively referred to as “danger signals,” coupled with failure to efficiently clear dead/dying cells, can elicit unresolved inflammation, accumulation of self-antigens, and adaptive leukocyte recruitment/activation. Collectively, these events can promote loss of immunological self-tolerance and onset/progression of autoimmunity. This review discusses critical molecular mechanisms by which exogenous particles (i.e., silica, asbestos, carbon nanotubes, titanium dioxide, aluminum-containing salts) and endogenous particles (i.e., monosodium urate, cholesterol crystals, calcium-containing salts) may promote unresolved inflammation and autoimmunity by inducing toxic responses in myeloid-lineage phagocytes with emphases on inflammasome activation and necrotic and programmed cell death pathways. A prototypical example is occupational exposure to respirable crystalline silica, which is etiologically linked to systemic lupus erythematosus (SLE) and other human autoimmune diseases. Importantly, airway instillation of SLE-prone mice with crystalline silica elicits severe pulmonary pathology involving accumulation of particle-laden alveolar macrophages, dying and dead cells, nuclear and cytoplasmic debris, and neutrophilic inflammation that drive cytokine, chemokine, and interferon-regulated gene expression. Silica-induced immunogenic cell death and danger signal release triggers accumulation of T and B cells, along with IgG-secreting plasma cells, indicative of ectopic lymphoid tissue neogenesis, and broad-spectrum autoantibody production in the lung. These events drive early autoimmunity onset and accelerate end-stage autoimmune glomerulonephritis. Intriguingly, dietary supplementation with ω-3 fatty acids have been demonstrated to be an intervention against silica-triggered murine autoimmunity. Taken together, further insight into how particles drive immunogenic cell death and danger signaling in myeloid-lineage phagocytes and how these responses are influenced by the genome will be essential for identification of novel interventions for preventing and treating inflammatory and autoimmune diseases associated with these agents.
... Innate immune dysregulation is the driver for auto-inflammatory diseases, which subsequently will lead to autoreactive T and B cell responses [11]. Indeed, the enhanced inflammatory response reflected by the increased levels of reactive oxygen species and nitric oxide as well as the over-expression of pro-inflammatory cytokines such as TNF-α, interleukin IL-6, IL-8 and IL-1β are essential features that might provide an "autoinflammatory" concept for BD [12,13,14,15]. ...
Behçet's disease is a chronic systemic inflammatory disorder associated with a cytokine profile disruption and increased nitric oxide levels. In our current study we sought to evaluate the in-vitro modulatory effect of nicotine, the principal alkaloid of tobacco, on nitric oxide (NO), interleukin 1β (IL-1β) and interleukin 37 (IL-37) production during Behçet's disease. Peripheral blood mononuclear cells cultures were performed with or without nicotine (200 μg/ml). Culture supernatants were harvested after 24 h of incubation. NO, IL-1β and IL-37 measurements were, respectively, performed by modified Griess method and ELISA sandwich. Our results showed that nicotine significantly reduced NO and IL-1β levels in patients with Behçet’s disease, while it increased IL-37 production. Our results showed no sex differences in the effects of nicotine on the production of nitric oxide and IL-1β nor IL-37 in PBMC of patients. Our findings suggest that nicotine may provide a potential therapeutic strategy targeting inflammation during Behçet’s disease.
... 11 rs10754558 and rs4353135 have been investigated in previous studies on gastric cancer and immune disorders, respectively. 12,13 In addition, rs6822844 in IL2 has been proven to be associated with plasma IL2 levels in breast cancer patients, making it a promising biomarker for immune status among cancer patients. 14 Considering the above associations between these SNPs and cancer and immune disorders, we speculated that these SNPs may also be involved in the occurrence and development of HNC. ...
Purpose
This study aimed to evaluate the associations between immune-related gene (FCRL3, NLRP3 and IL2) polymorphisms and the risk of head and neck cancer (HNC).
Methods
Six polymorphisms of FCRL3, NLRP3 and IL2 were genotyped in 400 HNC cases and 400 controls using a MassARRAY platform.
Results
rs11264799-T was a protective variant against HNC risk, while rs7528684-G, rs35829419-A and rs6822844-T were all risk alleles for HNC (p < 0.05). rs11264799-TT was correlated with reduced HNC risk, while rs7528684-GG and rs6822844-TG were associated with an elevated risk of disease (p < 0.05). Moreover, rs11264799 was correlated with a declining risk of HNC in three genetic models (p < 0.05). In contrast, rs7528684 exhibited an elevated risk of HNC in recessive and additive models; rs35829419 and rs6822844 were associated with an increased risk of disease in dominant and additive models (p < 0.05). Finally, an interaction was observed between the above SNPs and drinking (p < 0.05).
Conclusion
The results expand our knowledge on immune-related gene polymorphisms in HNC and provide clues for further functional study on the pathogenesis of HNC.
... Nevertheless, recent studies showed that major histocompatibility complex (MHC) regulatory variants confer more severe risk than HLA-coding variants particularly in early disease onset and in patients with family history [31,97]. Risk alleles analyses also found that these genes mediate innate immunity (CD80, IFIH1, NLRP1), drive adaptive immunity (CTLA4, FOXP3, PTPN22), implicate immune cell lysis and cell apoptosis (FASLG, GZMB, RERE, NEK6), and affect melanocyte function (TYR, PMEL, MC1R, IRF4, OCA2), supporting a role of immune network plays in the etiology of vitiligo [99,[101][102][103]. The encoding proteins or corresponding function of some susceptibility genes identified by GWAS still remains unknown, including FARP2-STK25, FBXO45-NRROS, SCAF1-IRF3-BCL2L12, and ZC3H7B-TEF [101]. ...
Vitiligo is an autoimmune disease of the skin characterized by epidermal melanocyte loss resulting in white patches, with an approximate prevalence of 0.5–2% worldwide. Several precipitating factors by chemical exposure and skin injury present commonly in patients with vitiligo. Although the diagnosis appears to be straightforward for the distinct clinical phenotype and specific histological features, vitiligo provides many challenges including chronicity, treatment resistance, frequent relapse, associated profound psychosocial effect, and negative impact on quality of life. Multiple mechanisms are involved in melanocyte disappearance, including genetics, environmental factors, and immune-mediated inflammation. Compelling evidence supports the melanocyte intrinsic abnormalities with poor adaptation to stressors leading to instability and release of danger signals, which will activate dendritic cells, natural killer cells, and innate lymphoid cells to initiate innate immunity, ultimately resulting in T-cell mediated adaptive immune response and melanocyte destruction. Importantly, the cross- talk between keratinocytes, melanocytes, and immune cells, such as interferon (IFN)-γ signaling pathway, builds inflammatory loops that give rise to the disease deterioration. Improved understanding of the immune pathogenesis of vitiligo has led to the development of new therapeutic options including Janus kinase (JAK) inhibitors targeting IFN-γ signaling pathways, which can effectively reverse depigmentation. Furthermore, definition of treatment goals and integration of comorbid diseases into vitiligo management have revolutionized the way vitiligo is treated. In this review, we highlight recent developments in vitiligo clinical aspects and immune pathogenesis. Our key objective is to raise awareness of the complexity of this disease, the potential of prospective therapy strategies, and the need for early and comprehensive management.
... 98 Recent studies have revealed that mouse p202 and human IFI16-β impede AIM2 inflammasome formation and stimulate IFN-β production. 84,[99][100][101] An altered AIM2 inflammasome system together with other IFN-inducible protein-mediated responses may trigger the pathogenesis of SLE. In line with this hypothesis, treatment of murine macrophages with IFN-α differentially modulates the levels of AIM2 and p202. ...
Absent in melanoma 2 (AIM2) is a novel member of interferon (IFN)-inducible PYHIN proteins. In innate immune cells, AIM2 servers as a cytoplasmic double-stranded DNA sensor, playing a crucial role in the initiation of the innate immune response as a component of the inflammasome. AIM2 expression is increased in patients with systemic lupus erythematosus (SLE), psoriasis, and primary Sjogren's syndrome, indicating that AIM2 might be involved in the pathogenesis of autoimmune diseases. Meanwhile, AIM2 also plays an antitumorigenesis role in an inflammasome independent-manner. In melanoma, AIM2 is initially identified as a tumor suppressor factor. However, AIM2 is also found to contribute to lung tumorigenesis via the inflammasome-dependent release of interleukin 1β and regulation of mitochondrial dynamics. Additionally, AIM2 reciprocally dampening the cGAS-STING pathway causes immunosuppression of macrophages and evasion of antitumor immunity during antibody treatment. To summarize the complicated effect and role of AIM2 in autoimmune diseases and cancers, herein, we provide an overview of the emerging research progress on the function and regulatory pathway of AIM2 in innate and adaptive immune cells, as well as tumor cells, and discuss its pathogenic role in autoimmune diseases, such as SLE, psoriasis, primary Sjogren's syndrome, and cancers, such as melanomas, non-small-cell lung cancer, colon cancer, hepatocellular carcinoma, renal carcinoma, and so on, hopefully providing potential therapeutic and diagnostic strategies for clinical use.
... The infiltration of immune cells and the release of pro-and anti-inflammatory cytokines is key to the pathogenesis of vitiligo. KEGG results showed that MDEGs were significantly enriched in IL-17 signaling pathway, Th17 cell differentiation, TNF signaling pathway, and NOD-like receptor signaling pathways, and these signaling pathways have been proved to be involved in mediating the immune regulation of vitiligo (18,27,28). In addition, differential methylation of AKT1, PYGB, HDAC2 were frequently observed in the insulin signaling and thyroid hormone signaling pathways. ...
Vitiligo is an pigmentation disorder caused by a variety of pathogenic factors; its main pathophysiological conditions include oxidative stress, immune activation, and genetic background. Additionally, DNA methylation is often associated with the pathogenesis of vitiligo; however, the underlying mechanism remains unknown. In the present study, we used the Human Methylation 850K BeadChip platform to detect DNA methylation changes in the vitiligo melanocytes. We then integrated the results with the transcriptome data of vitiligo melanocytes and lesions to analyse the correlation between differentially methylated levels and differentially expressed genes. The results showed that there was a significant negative correlation between methylation levels and differentially expressed genes. Subsequently, we enriched GO and KEGG based on methylated differentially expressed genes (MDEGs) using R package ClusterProfiler, and the results were closely related to the pathogenesis of vitiligo. In addition, we also constructed a PPI network of MDEGs and excavated three important functional epigenetic modules, involving a total of 12 (BCL2L1, CDK1, ECT2, HELLS, HSP90AA1, KIF23, MC1R, MLANA, PBK, PTGS2, SOX10, and TYRP1) genes. These genes affect melanocyte melanogenesis, cellular oxidative stress and other important biological processes. Our comprehensive analysis results support the significant contribution of the status of DNA methylation modification to vitiligo, which will help us to better understand the molecular mechanism of vitiligo and explore new therapeutic strategies.
... They can exist in many parts of the body, such as skin and blood vessels, and have complex mechanisms. It has been reported that inflammatory cytokines IL-1 β and IL-18 can induce Th17 response and endothelial cell damage, aggravate many autoimmune diseases (Yang and Chiang, 2015). Endothelial cells may be related to the pathogenesis of vitiligo, which needs further study. ...
Vitiligo is a common immune-related depigmentation condition, and its pathogenesis remains unclear. This study used a combination of bioinformatics methods and expression analysis techniques to explore the relationship between immune cell infiltration and gene expression in vitiligo. Previously reported gene expression microarray data from the skin (GSE53146 and GSE75819) and peripheral blood (GSE80009 and GSE90880) of vitiligo patients and healthy controls was used in the analysis. R software was used to filter the differentially expressed genes (DEGs) in each dataset, and the KOBAS 2.0 server was used to perform functional enrichment analysis. Compared with healthy controls, the upregulated genes in skin lesions and peripheral blood leukocytes of vitiligo patents were highly enriched in immune response pathways and inflammatory response signaling pathways. Immunedeconv software and the EPIC method were used to analyze the expression levels of marker genes to obtain the immune cell population in the samples. In the lesional skin of vitiligo patients, the proportions of macrophages, B cells and NK cells were increased compared with healthy controls. In the peripheral blood of vitiligo patients, CD8+ T cells and macrophages were significantly increased. A coexpression analysis of the cell populations and DEGs showed that differentially expressed immune and inflammation response genes had a strong positive correlation with macrophages. The TLR4 receptor pathway, interferon gamma-mediated signaling pathway and lipopolysaccharide-related pathway were positively correlated with CD4+ T cells. Regarding immune response-related genes, the overexpression of IFITM2, TNFSF10, GZMA, ADAMDEC1, NCF2, ADAR, SIGLEC16, and WIPF2 were related to macrophage abundance, while the overexpression of ICOS, GPR183, RGS1, ILF2 and CD28 were related to CD4+ T cell abundance. GZMA and CXCL10 expression were associated with CD8+ T cell abundance. Regarding inflammatory response-related genes, the overexpression of CEBPB, ADAM8, CXCR3, and TNIP3 promoted macrophage infiltration. Only ADORA1 expression was associated with CD4+ T cell infiltration. ADAM8 and CXCL10 expression were associated with CD8+ T cell abundance. The overexpression of CCL18, CXCL10, FOS, NLRC4, LY96, HCK, MYD88, and KLRG1, which are related to inflammation and immune responses, were associated with macrophage abundance. We also found that immune cells infiltration in vitiligo was associated with antigen presentation-related genes expression. The genes and pathways identified in this study may point to new directions for vitiligo treatment.
... Hence, these variants play a key role in the basic active state of the innate immune response. 46 On the other hand, the result of IL-1β blocked and/or inhibition of NLRP3 inflammasome for blocking of IL-1β and IL-18 are the first therapeutic purposes for RA treatment. 47 In vitro neutrophils carrying both the NLRP3 Q705K and the CARD8 C10X polymorphisms showed delayed apoptosis, suggesting that these variants have functional consequences, so that they might result in a deregulated innate immune response, and participate in the pathogenesis of RA. ...
... Several diseases are associated with the abnormal activation of the NLRP3 inflammasome, including type II diabetes, COVID-19, Alzheimer's disease, inflammatory bowel diseases, multiple sclerosis, and experimental autoimmuneencephalomyelitis (Cleophas et al., 2016;Legrand-Poels et al., 2014;Perricone et al., 2020;Yang and Chiang, 2015;Zaki et al., 2011). ...
Regulatory T cells induced by B cells (Treg-of-B cells), a distinct Foxp3⁻ Treg cell subset, have established the roles in the suppression of inflammatory conditions, including asthma and intestinal inflammation. However, little is known about the regulatory effects of Treg-of-B cells on innate immunity. Herein, we examined whether Treg-of-B cells could regulate macrophage function and prevent NLRP3-associated diseases, particularly inflammatory gouty arthritis. Treg-of-B cells, but not thymus-derived Treg or effector T cells, inhibited inflammasome-mediated IL-1β secretion, caspase-1 activation, and NLRP3 production by LPS/ATP stimulation in a cell contact-dependent manner. In addition, Treg-of-B cells inhibited monosodium urate-induced NLRP3 inflammasome activation in vitro via NF-κB signaling. Treg-of-B cells ameliorated gouty inflammation in a mouse air pouch model by reducing neutrophil and leukocyte influx and cytokine and chemokine production. Our results demonstrated that Treg-of-B cells exerted regulatory effects on innate immunity by suppressing NLRP3 inflammasome activation and feasible for future therapeutic applications.
... Dysregulated inflammasome activity has been implicated in hereditary and acquired inflammatory disorders (6). Variations in genes encoding proteins that are directly or indirectly involved in regulating inflammasome activity are associated with AS, including MEFV, CARD9, CARD15, IRGM, IL1R1, and IL1R2 (reviewed in [7]). ...
Objective
We undertook this study to evaluate the activation and functional relevance of inflammasome pathways in ankylosing spondylitis (AS) patients and rodent models and their relationship to dysbiosis.
Methods
An inflammasome pathway was evaluated in the gut and peripheral blood from 40 AS patients using quantitative reverse transcriptase–polymerase chain reaction (qRT‐PCR), immunohistochemistry (IHC), flow cytometry, and confocal microscopy, and was compared to that of 20 healthy controls and 10 patients with Crohn’s disease. Bacteria was visualized using silver stain in human samples, and antibiotics were administered to HLA–B27–transgenic rats. The NLRP3 inhibitor MCC950 was administered to SKG mice, and ileal and joint tissues were assessed by IHC analysis and real‐time qRT‐PCR. The role of inflammasome in modulating the interleukin‐23 (IL‐23)/IL‐17 axis was studied ex vivo.
Results
Expression levels of Nlrp3, Nlrc4, and Aim2 were increased in the gut of HLA–B27–transgenic rats and reduced by antibiotic treatment (P < 0.05). In curdlan‐treated SKG mice, NLRP3 blockade prevented ileitis and delayed arthritis onset (P < 0.05). Compared to healthy controls, AS patients demonstrated overexpression of NLRP3 (fold induction 2.33 versus 22.2; P < 0.001), NLRC4 (fold induction 1.90 versus 6.47; P < 0.001), AIM2 (fold induction 2.40 versus 20.8; P < 0.001), CASP1 (fold induction 2.53 versus 24.8; P < 0.001), IL1B (fold induction 1.07 versus 10.93; P < 0.001), and IL18 (fold induction 2.56 versus 15.67; P < 0.001) in the ileum, and caspase 1 activity was increased (P < 0.01). The score of adherent and invasive mucosa‐associated bacteria was higher in AS (P < 0.01) and correlated with the expression of inflammasome components in peripheral blood mononuclear cells (P < 0.001). NLRP3 expression was associated with disease activity (the Ankylosing Spondylitis Disease Activity Score using the C‐reactive protein level) (r² = 0.28, P < 0.01) and with IL23A expression (r² = 0.34, P < 0.001). In vitro, inflammasome activation in AS monocytes was paralleled by increased serum levels of IL‐1β and IL‐18. Induction of IL23A, IL17A, and IL22 was IL‐1β–dependent.
Conclusion
Inflammasome activation occurs in rodent models of AS and in AS patients, is associated with dysbiosis, and is involved in triggering ileitis in SKG mice. Inflammasomes drive type III cytokine production with an IL‐1β–dependent mechanism in AS patients.
... Die hierfür entscheidende Struktureinheit ist das Inflammasom, eine makromolekulare intrazelluläre Plattform, welche als ein angeborener Immunitätssensor fungiert [22]. Unter allen identifizierten Inflammasomen ist das NALP3-Inflammasom am besten charakterisiert. ...
Pericarditis is the term for inflammatory involvement of the pericardium, which can
be associated with pericardial effusion and myocardial involvement (perimyocarditis).
Pericarditis can be present in the context of systemic inflammatory rheumatic diseases but can also constitute a distinct disease entity. Idiopathic recurrent pericarditis (IRP) describes relapsing conditions of pericarditis with an unknown cause, which show essential common features with autoinflammatory diseases. This article gives an overview of the frequency of pericarditis in systemic rheumatic diseases. Moreover, the clinical manifestations and pathophysiology of IRP are discussed. Finally, the therapeutic algorithms for acute and idiopathic pericarditis are explained.
... Inflammasome is a multiprotein complex, which is activated by infection and injury and then which promotes the maturation of proinflammatory factors and participates in the innate immune response [10]. Inflammasomes are composed of three parts: (1) adaptor protein, that is, apoptosisassociated speck-like protein contains caspase activation recruitment domain (ASC); (2) caspase-1(CASP1), after activation; pro-IL-β and pro-IL-18 are sheared to form mature IL-1β and IL-18; (3) absent in melanoma 2-(AIM-2-) like receptor (ALR) or NOD-like receptor (NLR) forming stress signal receptors or framework proteins [10][11][12]. NLR family caspase recruitment domain-(CARD-) containing 4 (NLRC4) belongs to the NLR family and is mainly activated by Gram-negative bacteria containing a type III or type IV secretion system [13]. When infected with Salmonella and Legionella, NLRC4 inflammasomes are activated by recognizing their flagellins and T3SS proteins [14][15][16]. ...
Background:
Many studies have shown that NLRC4 inflammasome polymorphisms are associated with a variety of autoimmune diseases, but the associations between NLRC4 polymorphisms and autoimmune thyroid diseases (AITDs) are unclear. Our research was aimed at identifying the correlations between NLRC4 polymorphisms and AITDs.
Methods:
Hi-SNP high-throughput genotyping technology was used for detecting four single-nucleotide polymorphisms (SNPs) of NLRC4 in 1005 AITDs patients (including 629 Graves' disease and 376 Hashimoto's thyroiditis) and 781 healthy controls.
Results:
Compared with healthy controls, the allele frequencies and genotype distribution of rs385076 were statistically related to AITDs (P = 0.016 and P = 0.048, respectively) and Hashimoto's thyroiditis (P = 0.022 and P = 0.046, respectively). Before adjusting for age and gender, rs385076 and AITDs had a significant association in three models of allele model, dominant model, and homozygous model. After adjusting for age and gender, in the above three models, there is still a clear relationship between them. Before adjusting for age and gender, there were prominent discrepancy between rs385076 and Hashimoto's thyroiditis in the allele model (OR = 0.81, 95% CI 0.67-0.97; P = 0.021) and the dominant model (OR = 0.73, 95% CI 0.57-0.94; P = 0.014), after adjusting for age and gender, rs385076 and Hashimoto's thyroiditis were significantly related to allele model, dominant model, and homozygous model. However, rs455060, rs212704, and rs675712 were not related to AITDs in our study.
Conclusion:
NLRC4 rs385076 was found to have a significant association with Hashimoto's thyroiditis for the first time. It laid a foundation for the disclosure of the pathogenesis of AITDs, and provided a possible treatment prospect for HT.
... It is worth noting that aberrant NLRP3 inflammasome activity may cause a large number of pathological changes in neurological disorders, metabolic diseases and autoimmune diseases [29,30]. As previous studies stated, inappropriate NLRP3 inflammasome activities are involved in type 2 diabetes [31], graft-versus-host disease [32], obesity-induced asthma [33] and insulin resistance [34]. ...
The nucleotide-binding oligomerization domain (NOD)-like receptor containing pyrin domain 3 (NLRP3) inflammasome is a high-molecular-weight complex mediated by the activation of pattern-recognition receptors (PRRs) seed in innate immunity. Once NLRP3 is activated, the following recruitment of the adapter apoptosis-associated speck-like protein containing a caspase recruitment domain (CARD) (ASC) and procaspase-1 would be initiated. Cleavage of procaspase-1 into active caspase-1 then leads to the maturation of the precursor forms of interleukin (IL)-1β and IL-18 into biologically active IL-1β and IL-18. The activation of NLRP3 inflammasome is thought to be tightly associated with a regulator never in mitosis A (NIMA)-related kinase 7 (NEK7), apart from other signaling events such as K⁺ efflux and reactive oxygen species (ROS). Plus, the NLRP3 inflammasome has been linked to various metabolic disorders, chronic inflammation and other diseases. In this review, we firstly describe the cellular/molecular mechanisms of the NEK7-licensed NLRP3 inflammasome activation. Then we detail the potential inhibitors that can selectively and effectively modulate either the NEK7-NLRP3 complex itself or the related molecular/cellular events. Finally, we describe some inhibitors as promising therapeutic strategies for diverse diseases driven by NLRP3 inflammasome.
Macrophages play diverse roles in development, homeostasis, and immunity. Accordingly, the dysfunction of macrophages is involved in the occurrence and progression of various diseases, such as coronavirus disease 2019 and atherosclerosis. The protective or pathogenic effect that macrophages exert in different conditions largely depends on their functional plasticity, which is regulated via signal transduction such as Janus kinase–signal transducer and activator of transcription, Wnt and Notch pathways, stimulated by environmental cues. Over the past few decades, the molecular mechanisms of signaling pathways in macrophages have been gradually elucidated, providing more alternative therapeutic targets for diseases treatment. Here, we provide an overview of the basic physiology of macrophages and expound the regulatory pathways within them. We also address the crucial role macrophages play in the pathogenesis of diseases, including autoimmune, neurodegenerative, metabolic, infectious diseases, and cancer, with a focus on advances in macrophage‐targeted strategies exploring modulation of components and regulators of signaling pathways. Last, we discuss the challenges and possible solutions of macrophage‐targeted therapy in clinical applications. We hope that this comprehensive review will provide directions for further research on therapeutic strategies targeting macrophage signaling pathways, which are promising to improve the efficacy of disease treatment.
Juvenile systemic lupus erythematosus (JSLE) is a multifaceted multifactorial disorder with an unclear etiopathogenesis. Environmental factors, genetic factors, and dysregulated and defective immune system responses are known to have a role in JSLE etiopathogenesis. NLRP3 inflammasome, as an important contributor to immune-mediated inflammatory responses, is assumed to be involved in JSLE etiopathogenesis. To determine whether the NLRP3 genetic variants are altered in patients with JSLE. Fifty-three patients diagnosed with JSLE and 56 healthy sex-matched controls were studied. NLRP3 (C/G rs10754558, C/T rs3806265, C/T rs4612666, A/C rs35829419) gene polymorphisms were evaluated using a TaqMan single-nucleotide polymorphism assay. C allele at position rs3806265 was detected in higher frequencies in patients than in the control group (37.74% vs 23.21%, P-value = .028). At the genotype level at the same position, CT has a significantly higher frequency in patients than the healthy subjects (75.47% vs 46.43%, P-value = .003). The NLRP3 rs3806265 CT genotype was detected at a higher frequency in patients with JSLE than in the healthy control group.
Autoimmune skin diseases are understood as conditions in which the adaptive immune system with autoantigen-specific T cells and autoantibody-producing B cells reacting against self-tissues plays a crucial pathogenic role. However, there is increasing evidence that inflammasomes, which are large multiprotein complexes that were first described 20 years ago, contribute to autoimmune disease progression. The inflammasome and its contribution to the bioactivation of interleukins IL-1β and IL-18 play an essential role in combating foreign pathogens or tissue damage, but may also act as a pathogenic driver of myriad chronic inflammatory diseases when dysfunctionally regulated. Inflammasomes containing the NOD-like receptor family members NLRP1 and NLRP3 as well as the AIM2-like receptor family member AIM2 have been increasingly investigated in inflammatory skin conditions. In addition to autoinflammatory diseases, which are often associated with skin involvement, the aberrant activation of the inflammasome has also been implied in autoimmune diseases that can either affect the skin besides other organs such as systemic lupus erythematosus and systemic sclerosis or are isolated to the skin in humans. The latter include, among others, the T-cell mediated disorders vitiligo, alopecia areata, lichen planus and cutaneous lupus erythematosus as well as the autoantibody-driven blistering skin disease bullous pemphigoid. Some diseases are characterized by both autoinflammatory and autoimmune responses such as the chronic inflammatory skin disease psoriasis. Further insights into inflammasome dysregulation and associated pathways as well as their role in forming adaptive immune responses in human autoimmune skin pathology could potentially offer a new field of therapeutic options in the future.
This literature review discusses the new concept of pathogenesis of systemic immune-mediated inflammatory diseases (IMIDs), presents their classification and analyzes their association with ocular manifestations.
Here, we will discuss autoimmune diseases and diseases based on a hyperreactive immune system, the so-called allergic diseases. A few other diseases based on gene mutations will be included here, as they mimick autoimmune diseases. In autoimmune-induced interstitial lung disease, many different factors come together: a wide variety of immune reactions can cause a wide variety of tissue reactions, for example, circulating autoantibodies either capable or devoid of complement activation, circulating immune complexes including large insoluble immune complexes formed by idiotypic–anti-idiotypic antibody networks, activation of coagulation, metabolism of pro-inflammatory substances, involvement of different types of leukocytes, and not the least, drugs given for the relieve of symptoms. These drugs themselves can cause toxic or inflammatory side effects. Another aspect in autoimmune diseases lies within its dynamic: an acute phase is changed into a phase with declining symptoms, going into a resolving stage, again starting acute, but also can progress into a subacute and chronic phase. Each of these phases will be accompanied by a different histology. Acute hypersensitivity pneumonia/extrinsic allergic alveolitis and asthma have already been discussed in previous chapters; however, chronic hypersensitivity pneumonia is included here, as it comes in the form of fibrosing pneumonias. Allergic mycosis and drug allergies are also discussed.
Background
The coronavirus disease (COVID-19) is a pandemic disease that threatens worldwide public health, and rheumatoid arthritis (RA) is the most common autoimmune disease. COVID-19 and RA are each strong risk factors for the other, but their molecular mechanisms are unclear. This study aims to investigate the biomarkers between COVID-19 and RA from the mechanism of pyroptosis and find effective disease-targeting drugs.
Methods
We obtained the common gene shared by COVID-19, RA (GSE55235), and pyroptosis using bioinformatics analysis and then did the principal component analysis(PCA). The Co-genes were evaluated by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and ClueGO for functional enrichment, the protein-protein interaction (PPI) network was built by STRING, and the k-means machine learning algorithm was employed for cluster analysis. Modular analysis utilizing Cytoscape to identify hub genes, functional enrichment analysis with Metascape and GeneMANIA, and NetworkAnalyst for gene-drug prediction. Network pharmacology analysis was performed to identify target drug-related genes intersecting with COVID-19, RA, and pyroptosis to acquire Co-hub genes and construct transcription factor (TF)-hub genes and miRNA-hub genes networks by NetworkAnalyst. The Co-hub genes were validated using GSE55457 and GSE93272 to acquire the Key gene, and their efficacy was assessed using receiver operating curves (ROC); SPEED2 was then used to determine the upstream pathway. Immune cell infiltration was analyzed using CIBERSORT and validated by the HPA database. Molecular docking, molecular dynamics simulation, and molecular mechanics-generalized born surface area (MM-GBSA) were used to explore and validate drug-gene relationships through computer-aided drug design.
Results
COVID-19, RA, and pyroptosis-related genes were enriched in pyroptosis and pro-inflammatory pathways(the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome complex, death-inducing signaling complex, regulation of interleukin production), natural immune pathways (Network map of SARS-CoV-2 signaling pathway, activation of NLRP3 inflammasome by SARS-CoV-2) and COVID-19-and RA-related cytokine storm pathways (IL, nuclear factor-kappa B (NF-κB), TNF signaling pathway and regulation of cytokine-mediated signaling). Of these, CASP1 is the most involved pathway and is closely related to minocycline. YY1, hsa-mir-429, and hsa-mir-34a-5p play an important role in the expression of CASP1. Monocytes are high-caspase-1-expressing sentinel cells. Minocycline can generate a highly stable state for biochemical activity by docking closely with the active region of caspase-1.
Conclusions
Caspase-1 is a common biomarker for COVID-19, RA, and pyroptosis, and it may be an important mediator of the excessive inflammatory response induced by SARS-CoV-2 in RA patients through pyroptosis. Minocycline may counteract cytokine storm inflammation in patients with COVID-19 combined with RA by inhibiting caspase-1 expression.
Primary biliary cholangitis (PBC) is an autoimmune disease that involves chronic inflammation and injury to biliary epithelial cells. To identify critical genetic factor(s) in PBC patients, we performed whole-exome sequencing of five female siblings, including one unaffected and four affected sisters, in a multi-PBC family, and identified 61 rare heterozygote variants that segregated only within the affected sisters. Among them, we were particularly interested in caspase-10, for although several caspases are involved in cell death, inflammation and autoimmunity, caspase-10 is little known from this perspective. We generated caspase-10 knockout macrophages, and then investigated the obtained phenotypes in comparison to those of its structurally similar protein, caspase-8. Unlike caspase-8, caspase-10 does not play a role during differentiation into macrophages, but after differentiation, it regulates the process of inflammatory cell deaths such as necroptosis and pyroptosis more strongly. Interestingly, caspase-10 displays better protease activity than caspase-8 in the process of RIPK1 cleavage, and an enhanced ability to form a complex with RIPK1 and FADD in human macrophages. Higher inflammatory cell death affected the fibrotic response of hepatic stellate cells; this effect could be recovered by treatment with UDCA and OCA, which are currently approved for PBC patients. Our findings strongly indicate that the defective roles of caspase-10 in macrophages contribute to the pathogenesis of PBC, thereby suggesting a new therapeutic strategy for PBC treatment.
Background
Pyroptosis is a lytic pro-inflammatory programmed cell death mode that depends on caspase, inflammasome, and Gasdermin D (GSDMD). A growing number of studies have shown that pyroptosis is closely related to the pathophysiological mechanism of lung. The purpose of this study is to analyze the literature from Science Citation Index Expanded (SCI-expanded) of Web of Science Core Collection (WoSCC) and visualize the current trends and hotspots in the research of pyroptosis in lung disease.
Methods
On February 20, 2022, we retrieved all articles on pyroptosis in lung disease from SCI-expanded of WoSCC. Original articles and reviews published in English from 2007 to 2021 were included in the analysis. VOSviewer 1.6.17 and CiteSpace 5.8.R2 were used to analyze the retrieved data and visualize the results.
Result
1798 qualified original articles and reviews on pyroptosis in lung disease were included in the bibliometric analysis. So far, the research in this field is still in a period of growth, and the number of global publications has increased yearly. Among the 66 countries that have published relevant articles, China ranked first in the number of publications, and the USA ranked first in the number of cited articles. Holian,A. was the author with the largest number of articles, including 21 published. The University of California System in the USA was the organization with the largest number of articles, totaling 55. Frontiers in Immunology was the journal with the most publications in pyroptosis. After bibliometric analysis, the frequently used keywords are: “NOD-like receptor3 (NLRP3) inflammasome”, “inflammation”, “oxidative stress”, and “acute lung injury (ALI)”.
Conclusion
The research on pyroptosis in lung disease is in its growth stage. The information released in this article may help researchers better understand the hotspots and developmental trends in this field, the cooperation network information of authors, countries, and institutions, and the citation correlation between articles. With the in-depth study of the mechanism of pyroptosis, the focus has shifted to increasing research on the connections and influences of different diseases. So far, increasing attention has been paid to the research field of the relationship between ALI and pyroptosis related to COVID-19.
Obesity is strongly associated with chronic low-grade inflammation. Obese patients have an increased risk to develop thyroid autoimmunity and to became hypothyroid, suggesting a pathogenetic link between obesity, inflammation and autoimmunity. Moreover, type 2 diabetes and dyslipidemia, also characterized by low-grade inflammation, were recently associated with more aggressive forms of Graves’ ophthalmopathy. The association between obesity and autoimmune thyroid disorders may also go in the opposite direction, as treating autoimmune hyper and hypothyroidism can lead to weight gain. In addition, restoration of euthyroidism by L-T4 replacement therapy is more challenging in obese athyreotic patients, as it is difficult to maintain thyrotropin stimulation hormone (TSH) values within the normal range. Intriguingly, pro-inflammatory cytokines decrease in obese patients after bariatric surgery along with TSH levels. Moreover, the risk of thyroid cancer is increased in patients with thyroid autoimmune disorders, and is also related to the degree of obesity and inflammation. Molecular studies have shown a relationship between the low-grade inflammation of obesity and the activity of intracellular multiprotein complexes typical of immune cells (inflammasomes). We will now highlight some clinical implications of inflammasome activation in the relationship between obesity and thyroid disease.
The incidence of type 1 diabetes (T1D) has increased, coinciding with lifestyle changes that have likely altered the gut microbiota. Dysbiosis, gut barrier dysfunction, and elevated systemic inflammation consistent with microbial antigen exposure, have been associated with T1D susceptibility and progression. A 6-week, single-arm, open-label pilot trial was conducted to investigate whether daily multi-strain probiotic supplementation could reduce this familial inflammation in 25 unaffected siblings of T1D patients. Probiotic supplementation was well-tolerated as reflected by high participant adherence and no adverse events. Community alpha and beta diversity were not altered between the pre- and post-supplement stool samplings. However, LEfSe analyses identified post-supplement enrichment of the family Lachnospiraceae, producers of the anti-inflammatory short chain fatty acid butyrate. Systemic inflammation was measured by plasma-induced transcription and quantified with a gene ontology-based composite inflammatory index (I.I.com). Post-supplement I.I.com was significantly reduced and pathway analysis predicted inhibition of numerous inflammatory mediators and activation of IL10RA. Subjects with the greatest post-supplement reduction in I.I.com exhibited significantly lower CD4+ CD45RO+ (memory):CD4+ CD45RA+ (naïve) T-cell ratios after supplementation. Post-supplement IL-12p40, IL-13, IL-15, IL-18, CCL2, and CCL24 plasma levels were significantly reduced, while post-supplement butyrate levels trended 1.4-fold higher. Probiotic supplementation may modify T1D susceptibility and progression and warrants further study.
Objective: Multiple sclerosis (MS) is a chronic, inflammatory and neurodegenerative disease characterized with demyelination and axonal damage in central nervous system (CNS). Inflamasomes, which are important part of this inflammatory process, regulate maturation of proinflammatory cytokines. Infamazom complexes are thought to increase in MS attacks. We investigated role of inflammasome complexes (nod-like receptor protein 1 and 3) in serum and cerebrospinal fluid (CSF) levels for MS development. Methods: Eighteen clinically isolated syndrome (CIS), 19 relapsing remitting multiple sclerosis (RRMS) and 20 healthy control cases were included in the study. Nod-like receptor protein 1 and 3 (NLRP1, NLRP3), inflammasome complex levels and oligoclonal band (OCB) patterns of all the groups were measured in serum and CSF samples using Enzyme-Linked Immuno Sorbent Assay (ELISA) method. Results: Although NLRP1 and NLRP3 levels in both RRMS and CIS patients measured in serum and CSF were significantly higher than healthy control group, there was no statistically significant difference between RRMS and CIS patients. On the other hand, the levels of NLRP1 and NLRP3 in CSF were significantly higher in OCB pattern positive patients compared to the OCB pattern negative patients. Conclusion: In this pilot study, it is shown that NLRP1 and NLRP3 inflammasome complexes increased in CSF samples of MS cases and that this tendency occurred during or maybe before the first MS attack. As a result, it was thought that these complexes may have an effect on the formation of the OCB band.
The history of autoimmune diseases (ADs) in humans is more than a century (120 years) old. Within this period, we have seen significant development in the field in terms of their causes (genetics, diet, environmental factors, and the phenomenon of molecular mimicry) responsible for autoantibodies (AutoAbs) and self-reactive T cells. Also, new molecules and signaling pathways (different receptors and their ligands) controlling the immune response have played a significant role in the field. We have discovered various immune cells and their subtypes. Innate lymphoid cells (ILCs) are also one of these immune cells, came to the forefront of immunology in 2009 and 2010, with their discovery in both humans and mice. However, the natural killer (NK) cells, which belong to group 1 ILCs of ILCs have been discovered much earlier (1975) in laboratory mice. Also, the lymphoid tissue inducer (LTi) cells uncovered in 1997 belong to group 3 ILCs. Their discovery has revolutionized the immunology of different inflammatory and infectious diseases, including asthma and helminthic parasitic infections, along with bacterial and viral diseases. ILCs appear as lymphocytes morphologically but work as innate immune cells and express and secrete various immune molecules (cytokines and chemokines) that have the potential to maintain immune homeostasis. Any breach in the ILCs homeostasis has the potential to initiate autoinflammatory and ADs. The present chapter discusses the importance of different types of ILCs (group 1 ILCs, group 2 ILCs, and group 3 ILCs) as crucial components of the immune system, their role in immunity and inflammation, and their impact on different ADs.
Emerging evidence indicates that NOD-like receptor protein 3 (NLRP3) inflammasome-induced inflammation plays a critical role in the pathogenesis of rheumatoid arthritis (RA). Celastrol (Cel) is a quinone-methylated triterpenoid extracted from Tripterygium wilfordii that is used to treat RA. However, researchers have not determined whether Cel exerts anti-RA effects by regulating the activation of the NLRP3 inflammasome. In the present study, complete Freund’s adjuvant (CFA)- induced rats and human mononuclear macrophages (THP-1 cells) were used to explore the anti-RA effects of Cel and its underlying mechanism. Joint swelling, the arthritis index score, inflammatory cell infiltration, and synovial hyperplasia in CFA-induced rats were correspondingly reduced after Cel treatment. The secretion of interleukin (IL)-1β and IL-18 in the serum of CFA-induced rats and supernatants of THP-1 cells exposed to Cel was significantly decreased. These inhibitory effects occurred because Cel blocked the nuclear factor-kappa B (NF-κB) signaling pathway and inhibited the activation of the NLRP3 inflammasome. Furthermore, Cel inhibited reactive oxygen species (ROS) production induced by lipopolysaccharide (LPS) and adenosine triphosphate (ATP). We speculated that Cel relieves RA symptoms and inhibits inflammation by inhibiting the ROS-NF-κB-NLRP3 axis.
Inflammasomes are filamentous signaling platforms integral to innate immunity. Currently, little is known about how these structurally similar filaments recognize and distinguish one another. A cryo-EM structure of the AIM2 PYD filament reveals that the architecture of the upstream filament is essentially identical to that of the adaptor ASC PYD filament. In silico simulations using Rosetta and molecular dynamics followed by biochemical and cellular experiments consistently demonstrate that individual filaments assemble bidirectionally. By contrast, the recognition between AIM2 and ASC requires at least one to be oligomeric and occurs in a head-to-tail manner. Using in silico mutagenesis as a guide, we also identify specific axial and lateral interfaces that dictate the recognition and distinction between AIM2 and ASC filaments. Together, the results here provide a robust framework for delineating the signaling specificity and order of inflammasomes.
The balance of production and elimination of free radicals and reactive oxygen species is disturbed in the human body during a space flight. Oxidative stress is a common pathogenetic link in the violation of the functions and structure of various body tissues. The main cellular components, such as DNA, lipids, and proteins, undergo oxidative damage. In this study, proteomic methods were used to analyze the frequency of detection of oxidative post-translational modifications of blood plasma proteins obtained from Russian participants in International Space Station (ISS) flights. The effect of the oxidative modification detected after space flight on the functional features of protein groups that regulate the hemostasis and complement activation cascade is examined. According to published data, the increase in oxidative post-translational modifications of proteins in the hemostasis system affects not only the protein structure but also the fibrin formation, as well as its viscoelastic and biochemical properties. Oxygenation of proteins with oxidation-sensitive methionine residues, including apolipoprotein A-I, thrombomodulin, and von Willebrand factor, increases the risk of developing vascular diseases and thrombosis. Oxidized phospholipids are deposited in the vessel wall, potentiating atherosclerotic changes. It was shown that the oxidative modification of the key protein, clusterin, changed the regulation of the complement cascade, as well as the association of the immune system with the coagulation cascade.
The causes of the obesity crisis and its comorbidities have been at the center of intensive research for decades. Throughout this time, numerous mechanisms have been found to cause or modulate the progression of these pathologies. Together, they paint a complex web of interactors in which low grade chronical inflammation takes center stage. The inhibition of the inflammatory reaction present during obesity has been demonstrated to greatly limit the progression of its comorbidities. Understanding the mechanisms by which metabolic inflammation is induced and resolved is therefore of crucial importance for human health. In recent years, two very important breakthroughs have occurred in this field. These are the identification of the antiinflammatory lipid mediators called specialized proresolving mediators and the discovery of the NLRP3 inflammasome as an important mediator of metabolic inflammation. We offer an overview of how these elements modulate the inflammatory reaction in obesogenic conditions and their effects on the progression of pathologies related to obesity. This chapter covers the molecular pathways responsible for the synthesis of the main pro- and antiinflammatory lipid mediators produced from ω-3 and ω-6 fatty acids as well as their individual functions. Additionally, we review the molecular mechanisms and outcomes of NLRP3 priming and activation resulting in the maturation of crucial proinflammatory cytokines (IL-1β and IL-18).
The inflammatory microenvironment in the lesion is not conducive to the survival of stem cells. Improving the inflammatory microenvironment may be an alternative strategy to enhance the efficacy of stem cells. We evaluated the therapeutic effect and molecular mechanism of MG53 on LPS-induced damage in hUC-MSCs and C57/BL6 mice. MG53 significantly promoted the proliferation and migration of hUC-MSCs, protected hUC-MSCs against LPS-induced apoptosis and mitochondrial dysfunction, and reversed LPS-induced inflammatory cytokines release. Furthermore, MG53 combined with hUC-MSCs transplantation improved LPS-induced memory impairment and activated neurogenesis by promoting the migration of hUC-MSCs and enhancing β III-tubulin and DCX expression. MG53 protein combined with hUC-MSCs improved the M1/M2 phenotype polarization of microglia accompanied with lower iNOS expression and higher ARG1 expression. MG53 significantly suppressed the expression of TNF-, TLR4, NLRP3, Cleaved-Caspase1 and IL-1β to alleviate LPS-induced neuroinflammation on hUC-MSCs and C57/BL6 mice. In conclusion, our results indicated that MG53 could protect hUC-MSCs against LPS-induced inflammatory damage and facilitate their efficacy on LPS-treated C57/BL6 mice partly by inhibiting NLRP3/Caspase-1/IL-1β axis.
Rheumatoid arthritis is a chronic autoinflammatory disease that affects 1-2% of the world's population and is characterized by widespread joint inflammation. Interleukin-1 is an important mediator of cartilage destruction in rheumatic diseases, but our understanding of the upstream mechanisms leading to production of interleukin-1β in rheumatoid arthritis is limited by the absence of suitable mouse models of the disease in which inflammasomes contribute to pathology. Myeloid-cell-specific deletion of the rheumatoid arthritis susceptibility gene A20/Tnfaip3 in mice (A20(myel-KO) mice) triggers a spontaneous erosive polyarthritis that resembles rheumatoid arthritis in patients. Rheumatoid arthritis in A20(myel-KO) mice is not rescued by deletion of tumour necrosis factor receptor 1 (ref. 2). Here we show, however, that it crucially relies on the Nlrp3 inflammasome and interleukin-1 receptor signalling. Macrophages lacking A20 have increased basal and lipopolysaccharide-induced expression levels of the inflammasome adaptor Nlrp3 and proIL-1β. As a result, A20-deficiency in macrophages significantly enhances Nlrp3 inflammasome-mediated caspase-1 activation, pyroptosis and interleukin-1β secretion by soluble and crystalline Nlrp3 stimuli. In contrast, activation of the Nlrc4 and AIM2 inflammasomes is not altered. Importantly, increased Nlrp3 inflammasome activation contributes to the pathology of rheumatoid arthritis in vivo, because deletion of Nlrp3, caspase-1 and the interleukin-1 receptor markedly protects against rheumatoid-arthritis-associated inflammation and cartilage destruction in A20(myel-KO) mice. These results reveal A20 as a novel negative regulator of Nlrp3 inflammasome activation, and describe A20(myel-KO) mice as the first experimental model to study the role of inflammasomes in the pathology of rheumatoid arthritis.
Background:
The NLRP3-inflammasome, implicated in the pathogenesis of several inflammatory disorders, has been analysed in rheumatoid arthritis (RA).
Methods:
Relative gene expression of NLRP3-inflammasome components was characterised in PBMCs of 29 patients receiving infliximab. A total of 1278 Caucasian patients with RA from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS) cohort receiving tumour necrosis factor (TNF) antagonists (infliximab, adalimumab and etanercept) were genotyped for 34 single nucleotide polymorphisms (SNPs), spanning the genes NLRP3, MEFV and CARD8. Regression analyses were performed to test for association between genotype and susceptibility and treatment response (disease activity score across 28 joints (DAS28) and EULAR improvement criteria) at 6 months, with secondary expression quantitative trait loci (eQTL) analyses.
Results:
At baseline, gene expression of ASC, MEFV, NLRP3-FL, NLRP3-SL and CASP1 were significantly higher compared with controls whereas CARD8 was lower in the patients. Caspase-1 and interleukin-18 levels were significantly raised in patients with RA. SNPs in NLRP3 showed association with RA susceptibility and EULAR response to anti-TNF in the BRAGGSS cohort, and in monocytes but not B cells, in eQTL analysis of 283 healthy controls. CARD8 SNPs were associated with RA susceptibility and DAS28 improvement in response to anti-TNF and eQTL effects in monocytes and B cells.
Conclusions:
This study found evidence of modulation of the NLRP3-inflammasome in patients with RA prior to receiving infliximab and some evidence of association for SNPs at NLRP3 and CARD8 loci with RA susceptibility and response to anti-TNF. The SNPs associated with susceptibility/response are not the main eQTL variants for either locus, and the associations with treatment response require replication in an independent cohort.
Tissue injury initiates an inflammatory response through the actions of immunostimulatory molecules referred to as damage-associated molecular patterns (DAMPs). DAMPs encompass a group of heterogenous molecules, including intracellular molecules released during cell necrosis and molecules involved in extracellular matrix remodeling such as hyaluronan, biglycan, and fibronectin. Kidney-specific DAMPs include crystals and uromodulin released by renal tubular damage. DAMPs trigger innate immunity by activating Toll-like receptors, purinergic receptors, or the NLRP3 inflammasome. However, recent evidence revealed that DAMPs also trigger re-epithelialization upon kidney injury and contribute to epithelial-mesenchymal transition and, potentially, to myofibroblast differentiation and proliferation. Thus, these discoveries suggest that DAMPs drive not only immune injury but also kidney regeneration and renal scarring. Here, we review the data from these studies and discuss the increasingly complex connection between DAMPs and kidney diseases.
A decade of work shows that the core function of phagocytosis in engulfment and destruction of microorganisms is only a small facet of the full spectrum of roles for phagocytosis in the immune system. The regulation of phagocytosis and its outcomes by inflammatory pattern recognition receptors (PRRs) is now followed by new studies strengthening this concept and adding further complexity to the relationship between phagocytosis and innate immune signaling. Phagocytosis forms the platform for activation of distinct members of the Toll-like receptor family, and even dictates their signaling outcomes. In many cases, phagocytosis is a necessary precedent to the activation of cytosolic PRRs and assembly of canonical and non-canonical inflammasomes, leading to strong pro-inflammatory responses and inflammatory cell death.
The inflammasome is an intracellular multiprotein complex involved in the activation of caspase-1 and the processing of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18. The inflammasome in the central nervous system (CNS) is involved in the generation of an innate immune inflammatory response through IL-1 cytokine release and in cell death through the process of pyroptosis. In this review, we consider the different types of inflammasomes (NLRP1, NLRP2, NLRP3, and AIM2) that have been described in CNS cells, namely neurons, astrocytes, and microglia. Importantly, we focus on the role of the inflammasome after brain and spinal cord injury and cover the potential activators of the inflammasome after CNS injury such as adenosine triphosphate and DNA, and the therapeutic potential of targeting the inflammasome to improve outcomes after CNS trauma.Journal of Cerebral Blood Flow & Metabolism advance online publication, 8 January 2014; doi:10.1038/jcbfm.2013.227.
The production of IL-1β during the infection with Mycobacterium tuberculosis (Mtb) is important for successful host immune defense. In macrophages and dendritic cells the host cell inflammasome is crucial for generation of secreted IL-1β in response to Mtb infections. In these cell types Mtb infection only activates the NLRP3-inflammasome. New reports demonstrate that nitric oxide has an important function in the negative regulation of the NLRP3-inflammasome to reduce tissue damage during Mtb infections. The type I interferon, IFN-β, is induced after Mtb infections and can also suppress NLRP3-inflammasome activation. In contrast, IFN-β increases activity of the AIM2-inflammasome after infection with intracellular pathogens such as Francisella tularensis and Listeria monocytogenes. Recent results demonstrate that non-tuberculous mycobacteria but not virulent Mtb induce the AIM2-inflammasome in an IFN-β dependent matter. Indeed, Mtb inhibits AIM2-inflammasome activation via its ESX-1 secretion system. This novel immune evasion mechanism may help Mtb to allow the induction of low levels of IFN-β to suppress the NLRP3-inflammasome without activating the AIM2-inflammasome.
The NLRP3 inflammasome has been recognized as one of the key components of the innate immunity by sensing a diversity of insults. Inflammasome activation results in the maturation of the pro-inflammatory cytokines interleukin (IL)-1β and IL-18. Increased production of IL-1β is found in patients with gain-of-function polymorphisms in genes encoding the NLRP3 inflammasome. Since approximately 5% of the Swedish population are heterozygote carriers of these combined gene variants, their impact on inflammasome status and a relationship on disease development is therefore highly relevant to study. The present study investigates levels of inflammasome-produced cytokines as a measure of inflammasome activation in healthy individuals carrying Q705K polymorphism in the NLRP3 gene combined with C10X in the CARD8 gene.
Genotyping of 1006 healthy blood donors was performed for the polymorphisms Q705K in the NLRP3 and C10X in the CARD8 genes. IL-1β, IL-18, IL-33, as well as a number of other pro-inflammatory cytokines, were analyzed by Luminex or ELISA in plasma from individuals carrying the polymorphisms and in age and gender matched non-carrier controls.
The prevalence of the polymorphisms was in line with previous studies. Plasma levels of IL-1β and IL-33 were elevated among carriers of combined Q705K+C10X polymorphisms compared to controls, whereas no difference was found for IL-18 and the other cytokines measured. Moreover, carriers of C10X or Q705K per se had similar plasma levels of IL-1β as non-carriers. These data suggest that the combined polymorphisms create inflammasomes with increased basal activation state, which might provide a more favourable innate immune response. In spite of this, it could also represent the mechanisms by which the inflammatory loop is triggered into a long-term inflammatory phenotype.
Inflammasomes are key signalling platforms that detect pathogenic microorganisms and sterile stressors, and that activate the highly pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18. In this Review, we discuss the complex regulatory mechanisms that facilitate a balanced but effective inflammasome-mediated immune response, and we highlight the similarities to another molecular signalling platform - the apoptosome - that monitors cellular health. Extracellular regulatory mechanisms are discussed, as well as the intracellular control of inflammasome assembly, for example, via ion fluxes, free radicals and autophagy.
Purpose:
Lupus nephritis, a major cause of morbidity in patients with systemic lupus erythematosus (SLE), is generally thought to be induced by macrophage-mediated inflammation following deposition of various autoantibodies in kidneys. We previously reported that macrophage aberrant activation induced by activated lymphocyte-derived apoptotic DNA (apopDNA) have been found to play pathogenic roles in the immunodysregulation in lupus nephritis. However, DNA sensor(s) involved in apopDNA-induced macrophage activation and lupus nephritis remains largely undefined. Herein, we aimed to reveal the DNA sensor(s) involved in SLE disease.
Methods:
Correlation between the level of absent in melanoma 2 (AIM2), a cytoplasmic DNA receptor in the inflammasome pathway, and the clinical severity of SLE disease were analyzed in SLE patients as well as in lupus mice. Activated macrophages induced by apopDNA were analyzed by real-time PCR and western blot for AIM2 expression. After silencing of AIM2 via siRNA-mediated knockdown in vitro and in vivo, macrophage activation, inflammatory response, and SLE syndrome were assessed.
Results:
AIM2 expression was closely correlated with the severity of disease in SLE patients and in lupus mice. Importantly, AIM2 expression was significantly increased in apopDNA-induced macrophages and closely correlated with macrophage activation. Knockdown of AIM2 significantly blunted apopDNA-induced macrophage activation. Furthermore, blockade of AIM2 expression notably ameliorated SLE syndrome via impeding macrophage activation and dampening inflammatory response in apopDNA-induced lupus mice.
Conclusions:
Our results implied that AIM2 might act as an important DNA sensor and a potential biomarker for apopDNA-induced macrophage functional maturation and SLE disease.
The P2X7 receptor is a ligand-gated cationic channel receptor that is actived by ATP and normally expressed by a variety of immune system cells, including macrophages and lymphocytes. Because it leads to release of IL-1β and cell death by apoptosis or necrosis, it is a potential therapeutic target for a variety of autoimmune inflammatory diseases, such as systemic lupus erythematosus (SLE). The P2X7R gene is highly polymorphic, and many single-nucleotide polymorphisms (SNPs) have been detected. A case-control study was performed to investigate the associations of SNPs in the P2X7R gene (rs1718119, rs2230911 and rs3751143) with susceptibility to SLE in 535 Chinese SLE patients and 532 controls. Results showed that rs1718119 was associated with SLE; in particular carriers of the A allele and AA/AG/(AG+AA) genotypes were at lower risk of the disease [A versus G, P < 0.001, odds ratio (OR) = 0.543, 95% CI: 0.424-0.697; AG versus GG, P = 0.018, OR = 0.659, 95% CI: 0.466-0.931; AA versus GG, P = 0.011, OR = 0.176, 95% CI: 0.046-0.668; AG+AA versus GG, P = 0.004, OR = 0.607, 95% CI: 0.433-0.850], but no significant differences in rs2230911 and rs3751143 were observed between SLE patients and controls. Stratification of cases for the presence of nephritis showed that rs2230911 G allele and CG/(CG+GG) genotypes were at a lower risk of SLE with nephritis (LN) (G versus C, P = 0.011, OR = 0.640, 95% CI: 0.454-0.903; CG versus CC, P = 0.035, OR = 0.645, 95% CI: 0.429-0.970; GG versus CC, P = 0.101, OR = 0.349, 95% CI: 0.099-1.228; CG+GG versus CC, P = 0.015 OR = 0.612, 95% CI: 0.411-0.910), but rs1718119 and rs3751143 were not associated with LN. Analysis of the haplotypes revealed one haplotype (ACA) that appeared to be a significantly 'protective' haplotype (P = 0.009, OR = 0.708, 95% CI: 0.546-0.918) with SLE. The findings suggest that the P2X7R gene might contribute to SLE susceptibility in the Chinese population.
Inflammasomes are cytosolic sensors that detect pathogens and danger signals in the innate immune system. The NLRP3 inflammasome is currently the most fully characterized inflammasome and is known to detect a wide array of microbes and endogenous damage-associated molecules. Possible involvement of the NLRP3 inflammasome (or inflammasomes) in the development of multiple sclerosis (MS) was suggested in a number of studies. Recent studies showed that the NLRP3 inflammasome exacerbates experimental autoimmune encephalomyelitis (EAE), an animal model of MS, although EAE can also develop without the NLRP3 inflammasome. In this paper, we discuss the NLRP3 inflammasome in MS and EAE development.
Autophagy is a cellular mechanism for the sequestration and degradation of intracellular pathogens and compromised organelles, particularly damaged mitochondria. Autophagy also clears other cellular components, such as inflammasomes and cytokines, thus providing an important means of regulating inflammation. Defects in autophagy have been found by genetic association studies to confer susceptibility to several autoimmune and inflammatory disorders, particularly inflammatory bowel disease. Thus, the manipulation of autophagy in disease situations is of growing interest for therapeutic targeting; however, the involvement of autophagy in cellular homoeostasis, in normal immune function and in inflammation is manifold. An appreciation of the intricacies of the contributions of this process to inflammation, and how these are altered by various immune and environmental stimuli, is essential for the understanding and interpretation of studies of inflammation and the design of therapeutics exploiting the manipulation of autophagy. This review focuses on the known roles of autophagy in the induction and maintenance of inflammation and on its role in the aetiology and regulation of inflammatory and autoimmune disorders.Immunology and Cell Biology advance online publication, 15 January 2013; doi:10.1038/icb.2012.82.
Neutrophil extracellular traps (NETs) represent an important defense mechanism against microorganisms. Clearance of NETs is impaired in a subset of patients with systemic lupus erythematosus, and NETosis is increased in neutrophils and, particularly, in low-density granulocytes derived from lupus patients. NETs are toxic to the endothelium, expose immunostimulatory molecules, activate plasmacytoid dendritic cells, and may participate in organ damage through incompletely characterized pathways. To better understand the role of NETs in fostering dysregulated inflammation, we examined inflammasome activation in response to NETs or to LL-37, an antibacterial protein externalized on NETs. Both NETs and LL-37 activate caspase-1, the central enzyme of the inflammasome, in both human and murine macrophages, resulting in release of active IL-1β and IL-18. LL-37 activation of the NLRP3 inflammasome utilizes P2X7 receptor-mediated potassium efflux. NET and LL-37-mediated activation of the inflammasome is enhanced in macrophages derived from lupus patients. In turn, IL-18 is able to stimulate NETosis in human neutrophils. These results suggest that enhanced formation of NETs in lupus patients can lead to increased inflammasome activation in adjacent macrophages. This leads to release of inflammatory cytokines that further stimulate NETosis, resulting in a feed-forward inflammatory loop that could potentially lead to disease flares and/or organ damage.
There are several studies on the association of TLR9 polymorphisms with systemic lupus erythematosus (SLE) in different ethnicities; however, the results are inconsistent. Therefore, we studied the distribution of the TLR9 C > T (rs352140) polymorphism in patients with SLE (n = 254) and controls (n = 521) in a Polish population. We did not observe significant differences in the prevalence of the TLR9 C > T genotype and alleles between patients with SLE and controls. However, we found a contribution of the T/T and T/C genotypes to renal [OR = 2.949 (95 % CI = 1.523–5.711, p = 0.001), (p
corr = 0.017)] and immunologic disorders [OR = 2.938 (95 % CI 1.500–5.755, p = 0.0012), (p
corr = 0.0204)] in SLE patients. Moreover, we observed a significant association between the TLR9 T/T and T/C genotypes and the presence of anti-dsDNA Ab [OR = 3.682 (1.647–8.230, p = 0.001), (p
corr = 0.017)]. Our studies suggest that the TLR9 C > T (rs352140) polymorphism might contribute to renal and immunologic disorders and to the presence of anti-dsDNA Ab.
The abundance and activation of macrophages in the inflamed synovial membrane/pannus significantly correlates with the severity of rheumatoid arthritis (RA). Although unlikely to be the 'initiators' of RA (if not as antigen-presenting cells in early disease), macrophages possess widespread pro-inflammatory, destructive, and remodeling capabilities that can critically contribute to acute and chronic disease. Also, activation of the monocytic lineage is not locally restricted, but extends to systemic parts of the mononuclear phagocyte system. Thus, selective counteraction of macrophage activation remains as efficacious approach to diminish local and systemic inflammation, as well as to prevent irreversible joint damage. AP = activator protein; BST = bone marrow stromal antigen; DMARD = disease-modifying antirheumatic drug; EBER(s) = Epstein-Barr virus-encoded small nuclear RNA(s); GM-CSF = granulocyte–macrophage colony-stimulating factor; GRO = growth-related oncogene protein; HLA = human leucocyte antigen; MCP = monocyte chemoattractant protein; MIP = macrophage inflammatory protein; NF-κB = nuclear factor-κB; NO = nitric oxide; RA = rheumatoid arthritis; TGF = transforming growth factor; Th = T-helper (cell); TIMP = tissue inhibitor of metalloproteinase; TNF = tumour necrosis factor.
Inflammasomes are multi-protein complexes that control the production of pro-inflammatory cytokines such as IL-1β. Inflammasomes play an important role in the control of immunity to tumors and infections, and also in autoimmune diseases, but the mechanisms controlling the activation of human inflammasomes are largely unknown. We found that human activated CD4+CD45RO+ memory T-cells specifically suppress P2X7R-mediated NLRP3 inflammasome activation, without affecting P2X7R-independent NLRP3 or NLRP1 inflammasome activation. The concomitant increase in pro-IL-1β production induced by activated memory T-cells concealed this effect. Priming with IFNβ decreased pro-IL-1β production in addition to NLRP3 inflammasome inhibition and thus unmasked the inhibitory effect on NLRP3 inflammasome activation. IFNβ suppresses NLRP3 inflammasome activation through an indirect mechanism involving decreased P2X7R signaling. The inhibition of pro-IL-1β production and suppression of NLRP3 inflammasome activation by IFNβ-primed human CD4+CD45RO+ memory T-cells is partly mediated by soluble FasL and is associated with down-regulated P2X7R mRNA expression and reduced response to ATP in monocytes. CD4+CD45RO+ memory T-cells from multiple sclerosis (MS) patients showed a reduced ability to suppress NLRP3 inflammasome activation, however their suppressive ability was recovered following in vivo treatment with IFNβ. Thus, our data demonstrate that human P2X7R-mediated NLRP3 inflammasome activation is regulated by activated CD4+CD45RO+ memory T cells, and provide new information on the mechanisms mediating the therapeutic effects of IFNβ in MS.
The NLRP3 inflammasome is a multiprotein complex consisting of three kinds of proteins, NLRP3, ASC, and pro-caspase-1, and plays a role in sensing pathogens and danger signals in the innate immune system. The NLRP3 inflammasome is thought to be involved in the development of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). However, the mechanism by which the NLRP3 inflammasome induces EAE is not clear. In this study, we found that the NLRP3 inflammasome played a critical role in inducing T-helper cell migration into the CNS. To gain migratory ability, CD4(+) T cells need to be primed by NLRP3 inflammasome-sufficient antigen-presenting cells to up-regulate chemotaxis-related proteins, such as osteopontin, CCR2, and CXCR6. In the presence of the NLRP3 inflammasome, dendritic cells and macrophages also induce chemotactic ability and up-regulate chemotaxis-related proteins, such as α4β1 integrin, CCL7, CCL8, and CXCL16. On the other hand, reduced Th17 cell population size in immunized Nlrp3(-/-) and Asc(-/-) mice is not a determinative factor for their resistance to EAE. As currently applied in clinical interventions of MS, targeting immune cell migration molecules may be an effective approach in treating MS accompanied by NLRP3 inflammasome activation.
Systemic Lupus Erythematosus (SLE) typically affects females at far greater rates than males; however male SLE patients often have more severe disease than females. The gender disparities have been reported in clinical manifestations and in serological and hematological indices as well. In particular, SLE complicated with nephritis is more frequent in men than women, and several groups identified male gender as a risk factor for progression to renal failure. The specific differences in pathogenesis amongst genders have yet to be conclusively defined, though genetic, hormonal, and immune responses have been analyzed thus far. Further research is warranted to further elucidate these differences and permit the development of gender-tailored treatment regimens.
Background:
Systemic lupus erythematosus (SLE) is an autoimmune disease, with multiple genetic and environmental factors involving in its etiology. The toll-like receptor 9 (TLR9) gene has been reported to have important roles in the development and progression of SLE. We performed a case-control study to investigate the effects of 4 SNPs in the TLR9 gene in the development of SLE in Northern Chinese population.
Methods:
Four SNPs including rs187084, rs5743836, rs352139 and rs352140 were genotyped using the SNaPshot® method. A group of 430 SLE patients were compared to 424 normal controls. Data were analyzed by SPSS 17.0 and HaploView v 4.1 software.
Results:
The frequency distributions of SNP rs351240 and haplotype H2 (TGCT) and H3 (CATT) were found to differ significantly between patient and control groups (p<0.05), while other SNPs and haplotypes showed no significant difference between the two cohorts (p>0.05).
Conclusion:
The results revealed that variations in the TLR9 gene are associated with SLE, indicating that TLR9 may play an important role in the pathogenesis of SLE in the northern Chinese Han population.
Objective:
SLE is more prevalent in females, but may cause more severe organ damage in males. The underlying mechanism is incompletely understood. Since macrophage plays a key role in SLE pathogenesis, the present work aimed to investigate whether inflammasomes in male and female SLE macrophages are differentially activated.
Methods:
Macrophages were derived from peripheral blood mononuclear cells of SLE patients and healthy controls. Adenosine triphosphate-stimulated IL-1β in lipopolysaccharide-primed macrophages was measured via ELISA. Nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain-containing protein 3 (NLRP3) and absent in melanoma 2 (AIM2) mRNA expression in macrophages were determined by RT-PCR. We further genotyped SLE patients for single nucleotide polymorphisms of NLRP3 and an NLRP3 regulator caspase recruitment domain family, member 8 (CARD8).
Results:
ATP-induced IL-1β production was increased in macrophages of both male and female SLE patients. Overexpression of NLRP3 mRNA was detected in unstimulated female SLE macrophages, while CARD8 variant allele is associated with SLE susceptibility in males. Moreover, AIM2 mRNA expression in unstimulated macrophages was found to be elevated in male SLE patients, but decreased in female SLE patients. However, the autoantibody titre of dsDNA, an AIM2 ligand, is associated with SLE disease severity only in female patients.
Conclusion:
Our study shows for the first time that the NLRP3 inflammasome is hyperactivated in macrophages of both male and female SLE patients. The mechanisms underlying NLRP3 hyperactivation might be different between the sexes. Furthermore, the AIM2 inflammasome might also contribute sex-differentially to SLE pathogenesis and severity.
Background:
Recent studies have suggested that interleukin (IL)-18 gene (-137G/C) polymorphism is associated with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). However, other studies did not confirm this correlation.
Objective:
The objective of this study was to evaluate the relationships of IL-18 -137G/C and RA and SLE using a meta-analysis.
Methods:
Pubmed, Embase and Cochrane library databases were systemically searched. Data were extracted by two independent reviewers and pooled odds ratio (OR) with 95% confidence interval (CI) was calculated.
Results:
In RA, the overall ORs and 95% CIs of -137C were 1.03, 0.88-1.22 (p=0.391); 1.22, 0.89-1.68 (p=0.020) and 1.06, 0.93-1.21 (p=0.110) in dominant, recessive, and additive models, respectively. Furthermore, in SLE, the overall ORs and 95% CIs of -137C were 1.10, 0.94-1.29 (p=0.980); 1.21, 0.91-1.60 (p=0.010) and 1.10, 0.97-1.24 (p=0.454) in dominant, recessive, and additive models, respectively. IL-18 -137G/C could increase the risk of RA and SLE. No publication bias was found in this meta-analysis. After population stratification analysis, under recessive model, the pooled ORs and 95% CIs of -137C were 1.14, 0.82-1.60 (p=0.008) and 1.01, 0.66-1.55 (p=0.004) in European RA patients and Asian SLE patients, respectively.
Conclusions:
This meta-analysis showed that IL-18 -137G/C was a risk factor for RA and SLE, especially for RA in Europeans and SLE in Asians.
Toll-like receptors (TLRs) are positioned at the interface between innate and adaptive immunity. Unlike others, those such as TLR9, that recognize nucleic acids, are confined to the endosomal compartment and are scarce on the cell surface. Here, we present evidence for TLR9 expression on the plasma membrane of B cells. In contrast to endosomal TLR9, cell surface TLR9 does not bind CpG-B oligodeoxynucleotides. After B cell-receptor (BCR) stimulation, TLR9 was translocated into lipid rafts with the BCR, suggesting that it could serve as a co-receptor for BCR. Nevertheless, stimulation of B cells with anti-TLR9 antibodies did not modify the BCR-induced responses despite up-regulation of tyrosine phosphorylation of proteins. However, CpG-B activation of B cells, acting synergistically with BCR signals, was inhibited by anti-TLR9 stimulation. Induction of CD25 expression and proliferation of B cells were thus down-regulated by the engagement of cell surface TLR9. Overall, our results indicate that TLR9 expressed on the plasma membrane of B cells might be a negative regulator of endosomal TLR9, and could provide a novel control by which activation of autoreactive B cells is restrained.
Proinflammatory cytokines with immunosuppressive properties play an important role in the pathogenesis of multiple sclerosis (MS). Interleukin 18 (IL-18) is one of the most important innate cytokines produced from macrophages in the early stages of the inflammatory immune response. The purpose of this study was to determine whether there was any relationship between IL18 gene polymorphisms and MS. IL18 genotyping were performed in 101 MS patients and 164 control subjects by using the PCR-restriction fragment length polymorphism (PCR-RFLP) method. The frequency of MS patients with the CC genotype of the IL18 gene at position -137 was significantly higher than with the GG genotype [p = 0.01, odds ratio (OR) 3.17]. In haplotype analysis of two SNPs in the IL18 gene, frequency of the CC haplotype was significantly higher in MS patients (p = 0.002, OR 3.0). However, the genotype distribution of the IL18 -607 C/A polymorphism in the MS patient group was not significantly different from that of the control group. These data suggest that IL18 gene polymorphisms at position -137 might be a genetic risk factor for MS in the Turkish population.
Microglia and macrophages in the CNS contain multimolecular complexes termed inflammasomes. Inflammasomes function as intracellular sensors for infectious agents as well as for host-derived danger signals that are associated with neurological diseases, including meningitis, stroke and Alzheimer's disease. Assembly of an inflammasome activates caspase 1 and, subsequently, the proteolysis and release of the cytokines interleukin-1β and interleukin-18, as well as pyroptotic cell death. Since the discovery of inflammasomes in 2002, there has been burgeoning recognition of their complexities and functions. Here, we review the current understanding of the functions of different inflammasomes in the CNS and their roles in neurological diseases.
SLE is an autoimmune condition characterized by loss of tolerance to chromatin constituents and the production of ANAs. The
majority of SLE patients display spontaneous expression of type I IFN-induced genes in circulating mononuclear cells and peripheral
tissues, and type I IFNs play a role in the pathogenesis of the disease via the sustained activation of autoreactive T and
B cells necessary for the production of pathogenic autoantibodies. Several IFN-blocking strategies are currently being evaluated
in clinical trials: monoclonal antibodies directed against IFN-α and type I IFN-α receptor (IFNAR), as well as active immunization
against IFN-α. This review describes the rationale behind these trials and the results obtained, and discusses the perspectives
for further development of these drugs.
Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by periepithelial lymphocytic infiltrates in affected tissues and the production of plethora of autoantibodies. Among them autoimmune responses against Ro/SSA and La/SSB are of major importance since their detection is routinely used for disease diagnosis and clinical characterization. Although the exact mechanisms underlying disease pathogenesis are not fully understood, the important role of salivary gland epithelial cells (SGEC) in the initiation and development of the local immune responses is well-established. SGECs are also capable to mediate the exposure of the Ro/SSA and La/SSB autoantigens to the immune system by elevated apoptosis and autoantigen release in apoptotic bodies and/or by the secretion of autoantigen-containing exosomes. The expression of these autoantigens in epithelial cells appears to be tightly regulated. Up-to-date, signaling of certain innate immunity receptors, such as TLR3, appear to be implicated in the regulation of Ro/SSA and La/SSB expression by SGECs, whereas the deregulated expression of certain miRNAs that are predicted to target them in SS patients suggests a regulatory feedback at the post-transcriptional level. In the periphery, the humoral autoimmune responses are further regulated by the development of an active network of idiotypic-antiidiotypic antibodies. The plethora of mechanisms suggests that autoimmune humoral responses in SS are tightly regulated. In this review, the major humoral autoimmune responses, recent advances on the role of epithelial cells in their development, as well as possible regulatory mechanisms will be discussed.
Objectives:
An elevated interleukin (IL)-1β response in peripheral blood mononuclear cells (PBMCs) has been observed in systemic juvenile idiopathic arthritis (sJIA), suggesting a role for inflammasomes in the pathogenesis of JIA. We aimed to determine whether genetic polymorphisms of the NLRP3 inflammasome components confer risk for oligoarticular and polyarticular JIA in a Taiwanese population.
Method:
A total of 118 JIA patients and 103 healthy controls were genotyped for rs4353135 OR2B11/NLRP3 and rs2043211 CARD8 polymorphisms. Clinical laboratory data and serum IL-1β of JIA patients were evaluated by medical chart review and enzyme-linked immunosorbent assay (ELISA), respectively. The production of IL-17 in lymphocytes of different genotype carriers was measured using flow cytometry.
Results:
The variant rs4353135 G allele carrier conferred increased risk for oligoarticular and polyarticular JIA. The G allele was also found to be associated with higher levels of clinical inflammatory markers. Moreover, G variant carriers enhanced the lymphocyte IL-17 response. The G/G genotype further increased the need for treatment with the tumour necrosis factor (TNF) inhibitor etanercept.
Conclusions:
Our data indicate that the rs4353135 OR2B11/NLRP3 polymorphism might be functional in, and could contribute to, the pathophysiology of oligoarticular and polyarticular JIA in a Taiwanese population.
A major function of a subfamily of NLR (nucleotide-binding domain, leucine-rich repeat containing, or NOD-like receptor) proteins is in inflammasome activation, which has been implicated in a multitude of disease models and human diseases. This work will highlight key progress in understanding the mechanisms that activate the best-studied NLRs (NLRP3, NLRC4, NAIP, and NLRP1) and in uncovering inflammasome NLRs.
