Immunology in the Clinic Review Series: Focus on autoinflammatory diseases: inflammasomes: mechanisms of activation

Institute for Clinical Chemistry and Clinical Pharmacology, Unit for Clinical Biochemistry, University Hospital, University of Bonn, Bonn, Germany.
Clinical & Experimental Immunology (Impact Factor: 3.04). 03/2012; 167(3):369-81. DOI: 10.1111/j.1365-2249.2011.04534.x
Source: PubMed


Allergy, Host Responses, Cancer, Type 1 diabetes and viruses, Metabolic diseases.
Initiation of a successful immune response requires a working set of sensors that detect any noxious agent within the cellular microenvironment and molecular platforms that process this signal to trigger an appropriate effector response. Pattern recognition receptors can engage different signalling cascades that lead to proinflammatory gene expression. At the same time, transcription-independent events such as activation of proteases and/or phagocytosis are also initiated. The inflammasome pathway constitutes a signalling platform that leads to the activation of so-called inflammatory caspases, most notably caspase-1, which plays a pivotal role in the cleavage and thus maturation of proinflammatory cytokines, but also in the induction of pyroptosis, a special type of cell death. In this review we elaborate on the currently known inflammasome complexes with a special focus on the mechanism behind their activation. Understanding these mechanisms could provide important information regarding the potential signalling nodes that might be targeted for therapeutic intervention.

Download full-text


Available from: Andriy V Kubarenko, Feb 28, 2015
17 Reads
  • Source
    • "NF-κB is known to induce the transcription of pro-inflammatory cytokines and chemokines, like tumor necrosis factor-α (TNFα), monocyte chemotactic protein-1 (MCP1) and interleukin-1-beta (IL-1β) [16], [17], all of which are increased in alcohol-induced neuroinflammation [2], [3], [18]. Posttranslational cleavage of pro-IL-1β to mature IL-1β is required for its functional activity and is executed by the inflammasome via caspase-1 activation [19]. TLR activation via danger or pathogen associated molecular patterns (DAMPs and PAMPs) leads to NF-κB activation and consequently increased cytokine production [16]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Alcohol-induced neuroinflammation is mediated by pro-inflammatory cytokines and chemokines including tumor necrosis factor-α (TNFα), monocyte chemotactic protein-1 (MCP1) and interleukin-1-beta (IL-1β). Toll-like receptor-4 (TLR4) pathway induced nuclear factor-κB (NF-κB) activation is involved in the pathogenesis of alcohol-induced neuroinflammation. Inflammation is a highly regulated process. Recent studies suggest that microRNAs (miRNAs) play crucial role in fine tuning gene expression and miR-155 is a major regulator of inflammation in immune cells after TLR stimulation. To evaluate the role of miR-155 in the pathogenesis of alcohol-induced neuroinflammation. Wild type (WT), miR-155- and TLR4-knockout (KO) mice received 5% ethanol-containing or isocaloric control diet for 5 weeks. Microglia markers were measured by q-RTPCR; inflammasome activation was measured by enzyme activity; TNFα, MCP1, IL-1β mRNA and protein were measured by q-RTPCR and ELISA; phospho-p65 protein and NF-κB were measured by Western-blotting and EMSA; miRNAs were measured by q-PCR in the cerebellum. MiR-155 was measured in immortalized and primary mouse microglia after lipopolysaccharide and ethanol stimulation. Chronic ethanol feeding up-regulated miR-155 and miR-132 expression in mouse cerebellum. Deficiency in miR-155 protected mice from alcohol-induced increase in inflammatory cytokines; TNFα, MCP1 protein and TNFα, MCP1, pro-IL-1β and pro-caspase-1 mRNA levels were reduced in miR-155 KO alcohol-fed mice. NF-κB was activated in WT but not in miR-155 KO alcohol-fed mice. However increases in cerebellar caspase-1 activity and IL-1β levels were similar in alcohol-fed miR-155-KO and WT mice. Alcohol-fed TLR4-KO mice were protected from the induction of miR-155. NF-κB activation measured by phosphorylation of p65 and neuroinflammation were reduced in alcohol-fed TLR4-KO compared to control mice. TLR4 stimulation with lipopolysaccharide in primary or immortalized mouse microglia resulted in increased miR-155. Chronic alcohol induces miR-155 in the cerebellum in a TLR4-dependent manner. Alcohol-induced miR-155 regulates TNFα and MCP1 expression but not caspase-dependent IL-1β increase in neuroinflammation.
    PLoS ONE 08/2013; 8(8):e70945. DOI:10.1371/journal.pone.0070945 · 3.23 Impact Factor
  • Source
    • "Activation of IL-1β by an inflammasome is required to efficiently control viral, bacterial, and fungal pathogen infections. However, excess IL-1β activity contributes to a variety of diseases [72]. The NLRP3 inflammasome has been shown to play a central role in the pathogenesis of autoinflammatory disorders; its activity has also been implicated in diseases such as Alzheimer's disease, cancer, type II diabetes, and most recently AMD [71, 73, 74]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Age-related macular degeneration (AMD) is the leading cause of blindness in developed countries; with the aging population, the negative health impacts and costs of the disease will increase dramatically over the next decade. Although the exact cause of AMD is unknown, genetic studies have implicated the complement system as well as other immune responses in disease pathogenesis and severity. Furthermore, histologic studies have shown the presence of macrophages, lymphocytes, and mast cells, as well as fibroblasts, in both atrophic lesions and with retinal neovascularization. This review summarizes discussions from the fifth annual conference of the Arnold and Mabel Beckman Initiative for Macular Research by the Inflammation and Immune Response Task Force. These deliberations focused on the role of inflammatory immune responses, including complement, inflammasomes, adaptive immune responses, and para-inflammation, unanswered questions and studies to address these questions, and potential immune-related therapeutic targets for AMD.
    05/2013; 2013(5):348092. DOI:10.1155/2013/348092
  • Source
    • "A recent body of data revealed that needle-like particulate material (i.e., silica and MSU crystals, and fibrillar amyloid-β) activates the NLRP3 inflammasome [35], [38], [47]. Under resting conditions, NLRP3 is expressed but a pro-inflammatory signal is required to induce its expression to a level that leads to its activation [48]. Therefore, we decided to verify whether αSyn F increased the expression of NLRP3: in monocytes exposed to αSyn F, we measured the induction of mRNA encoding NLRP3 and compared it with that of NLRP1 (Fig. 2B). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Parkinson's disease (PD) is one of the most common neurodegenerative diseases. It is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta of the brain. Another feature is represented by the formation in these cells of inclusions called Lewy bodies (LB), principally constituted by fibrillar α-synuclein (αSyn). This protein is considered a key element in the aetiology of a group of neurodegenerative disorders termed synucleinopathies, which include PD, but the cellular and molecular mechanisms involved are not completely clear. It is established that the inflammatory process plays a crucial role in the pathogenesis and/or progression of PD; moreover, it is known that aggregated αSyn, released by neurons, activates microglia cells to produce pro-inflammatory mediators, such as IL-1β. IL-1β is one of the strongest pro-inflammatory cytokines; it is produced as an inactive mediator, and its maturation and activation requires inflammasome activation. In particular, the NLRP3 inflammasome is activated by a wide variety of stimuli, among which are crystallized and particulate material. In this work, we investigated the possibility that IL-1β production, induced by fibrillar αSyn, is involved the inflammasome activation. We demonstrated the competence of monomeric and fibrillar αSyn to induce synthesis of IL-1β, through TLR2 interaction; we found that the secretion of the mature cytokine was a peculiarity of the fibrillated protein. Moreover, we observed that the secretion of IL-1β involves NLRP3 inflammasome activation. The latter relies on the phagocytosis of fibrillar αSyn, followed by increased ROS production and cathepsin B release into the cytosol. Taken together, our data support the notion that fibrillar αSyn, likely released by neuronal degeneration, acts as an endogenous trigger inducing a strong inflammatory response in PD.
    PLoS ONE 01/2013; 8(1):e55375. DOI:10.1371/journal.pone.0055375 · 3.23 Impact Factor
Show more