May 2024
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31 Reads
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1 Citation
Cytotherapy
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May 2024
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31 Reads
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1 Citation
Cytotherapy
March 2024
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49 Reads
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1 Citation
High level expression of the pro‐inflammatory cytokine macrophage migration inhibitory factor (MIF) has been associated with severe asthma. The role of MIF and its functional promotor polymorphism in innate immune training is currently unknown. Using novel humanized CATT7 MIF mice, this study is the first to investigate the effect of MIF on bone marrow‐derived macrophage (BMDM) memory after house dust mite (HDM) challenge. CATT7 BMDMs demonstrated a significant primed increase in M1 markers following HDM and LPS stimulation, compared to naive mice. This M1 signature was found to be MIF‐dependent, as administration of a small molecule MIF inhibitor, SCD‐19, blocked the induction of this pro‐inflammatory M1‐like phenotype in BMDMs from CATT7 mice challenged with HDM. Training naive BMDMs in vitro with HDM for 24 h followed by a rest period and subsequent stimulation with LPS led to significantly increased production of the pro‐inflammatory cytokine TNFα in BMDMs from CATT7 mice but not WT mice. Addition of the pan methyltransferase inhibitor MTA before HDM training significantly abrogated this effect in BMDMs from CATT7 mice, suggesting that HDM‐induced training is associated with epigenetic remodelling. These findings suggest that trained immunity induced by HDM is under genetic control, playing an important role in asthma patients with the high MIF genotypes (CATT6/7/8).
December 2023
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19 Reads
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3 Citations
MicroRNA (miRNA)‐mediated mRNA regulation directs many homeostatic and pathological processes, but how miRNAs coordinate aberrant esophageal inflammation during eosinophilic esophagitis (EoE) is poorly understood. Here, we report a deregulatory axis where microRNA‐155 (miR‐155) regulates epithelial barrier dysfunction by selectively constraining tight junction CLDN7 (claudin‐7). MiR‐155 is elevated in the esophageal epithelium of biopsies from patients with active EoE and in cell culture models. MiR‐155 localization using in situ hybridization (ISH) in patient biopsies and intra‐epithelial compartmentalization of miR‐155 show expression predominantly within the basal epithelia. Epithelial miR‐155 activity was evident through diminished target gene expression in 3D organotypic cultures, particularly in relatively undifferentiated basal cell states. Mechanistically, generation of a novel cell line with enhanced epithelial miR‐155 stable overexpression induced a functionally deficient epithelial barrier in 3D air–liquid interface epithelial cultures measured by transepithelial electrical resistance (TEER). Histological assessment of 3D esophageal organoid cultures overexpressing miR‐155 showed notable dilated intra‐epithelial spaces. Unbiased RNA‐sequencing analysis and immunofluorescence determined a defect in epithelial barrier tight junctions and revealed a selective reduction in the expression of critical esophageal tight junction molecule, claudin‐7. Together, our data reveal a previously unappreciated role for miR‐155 in mediating epithelial barrier dysfunction in esophageal inflammation.
May 2023
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17 Reads
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4 Citations
AJP Gastrointestinal and Liver Physiology
MicroRNAs (miRNAs) are a class of small endogenous RNA molecules between 18 to 25 nucleotides long. The primary function of miRNAs is in the posttranscriptional regulation of mRNA targets through RNA interference culminating in mRNA degradation or translational repression. MiRNAs are fundamental in physiological and pathological processes such as, cell proliferation, differentiation, apoptosis, and inflammation. Among this includes the uncovered potential of miRNAs in overall esophageal disease with a focus on the clinicopathologic allergic disease eosinophilic esophagitis (EoE), gastroesophageal reflux disease (GERD) and the tumorigenic continuum from Barrett's esophagus towards esophageal adenocarcinoma (EAC). Although these pathologies are distinct from one another, they share pathophysiological elements such as an intense inflammatory milieu, esophageal dysfunction, and, as presented in this review, an overlap in miRNA expression which contributes to overall esophageal disease. The overlap in the dysregulated miRNA transcriptome of these pathologies highlights the key role miRNAs play in contributing to esophageal disease progression. Owing to this notable dysregulation, there is an attractive utility for miRNAs as less-invasive diagnostic and prognostic biomarkers in esophageal diseases which already require invasive endoscopies and biopsy retrieval. In this review, miRNAs within EoE, GERD, BE, EAC and esophageal achalasia are discussed, as well as reviewing a core set of miRNAs shared in the disease progression among some of these pathologies, as well as the potential utility of targeting miRNAs as therapeutic options in overall esophageal disease.
December 2022
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44 Reads
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6 Citations
Journal of Investigative Dermatology
January 2022
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108 Reads
Mucosal Associated Invariant T cells are a population of innate T cells, which express the invariant T cell receptor (TCR) alpha chain Va7.2 and are capable of robust rapid cytokine secretion, producing a milieu of cytokines including IFN-gamma; and IL-17. MAIT cells have been reported in multiple human tissues including the gut, periphery and skin. On-going research has highlighted their involvement in numerous inflammatory diseases ranging from rheumatoid arthritis and obesity to psoriasis. Hidradenitis Suppurativa (H.S) is a chronic inflammatory disease of the hair follicles, resulting in painful lesions of apocrine-bearing skin. Several inflammatory cytokines have been implicated in the pathogenesis of H.S including IL-17. The role of MAIT cells in H.S is currently unknown. In this study we show for the first time, that MAIT cells are altered in the peripheral blood of patients with H.S, with reduced frequencies and an IL-17 cytokine bias. We show that CCL20 expression is elevated in lesions of patients with H.S, and MAIT cells can actively traffic towards lesions via CCL20. We show that MAIT cells can accumulate in the lesions from patients with H.S. when compared to adjacent skin, with an IL-17 bias. We show that elevated IL-17, can be linked to the activation of dermal fibroblasts, promoting the expression of chemotactic signals including CCL20 and CXCL1. Finally, we show that targeting the IL-17A transcription factor RORyt robustly reduces IL-17 production by MAIT cells from patients with H.S. Collectively our data details IL-17 producing MAIT cells as a novel player in the pathogenesis of H.S and highlights the potential of RORyt inhibition as a novel therapeutic strategy.
... We have demonstrated exacerbated HDM-induced airway inflammation in mice expressing the human MIF CATT 7 allele [4,6]. Recently, using in vitro assays and an in vivo model of trained immunity, we identified a novel role for the high-expression MIF CATT 7 allele in significantly enhancing HDM-induced trained immunity in mouse bone marrow-derived macrophages (BMDMs) [5]. ...
March 2024
... MiRs are a short RNA fragment that control biologic processes including allergic responses. Mechanistically, these molecules may participate in the generation of the associated pathogenetic immune response or healing in EoE [45][46][47][48]. In a study of 22 adults, measurements of MiR-4688 was found to associate with the diagnosis of EoE [49]. ...
December 2023
... MiRNA is non-coding RNA that can regulate the transcription or post-transcriptional stability of mRNA, and participate in a series of physiological activities of cells, including metabolism, cell differentiation, etc. [24][25][26]. MiRNAs play critical roles in guiding changes in your cell's transcripts and subsequently its form and functions during EMT [27][28][29]. This study aims to further clarify the biological effects of miR-1199-5p targeting SRD5A2 on the regulation of hypospadias cells and the molecular mechanism of EMT transformation. ...
May 2023
AJP Gastrointestinal and Liver Physiology
... A similar finding was published in the case of patients with a chronic HIV-1 infection, where Vα7.2 + /CD161 − accumulated and MAIT cells decreased compared to in uninfected healthy controls, despite an unchanged total T cell number [13]. The active roles of MAIT cell subsets were identified in the pathogenesis of skin diseases, such as psoriasis and hidradenitis suppurativa, where they were found to be another alternative source of IL-17, increasing the severity of disease [14,15]. ...
December 2022
Journal of Investigative Dermatology