Lack of the pH-sensing Receptor TDAG8 [GPR65] in Macrophages Plays a Detrimental Role in Murine Models of Inflammatory Bowel Disease
| Autor: | Tcymbarevich I, Richards S, Russo G, Kuhn-Georgijevic J, Cosin-Roger J, Baebler K, Lang S, Bengs S, Atrott K, Bettoni C, Gruber S, Frey-Wagner I, Scharl M, Misselwitz B, Wagner C, Seuwen K, Rogler G, Ruiz P, Spalinger M, de Valliere C |
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| Rok vydání: | 2019 |
| Předmět: | |
| Zdroj: | JOURNAL OF CROHNS & COLITIS r-FISABIO. Repositorio Institucional de Producción Científica instname |
| ISSN: | 1873-9946 |
| Popis: | Background: Tissue inflammation in inflammatory bowel diseases [IBD] is associated with local acidification. Genetic variants in the pH-sensing G protein-coupled receptor 65, also known as T cell death-associated gene 8 [TDAG8], have been implicated in IBD and other autoimmune diseases. Since the role of TDAG8 in intestinal inflammation remains unclear, we investigated the function of TDAG8 using murine colitis models. Methods: The effects of TDAG8 deficiency were assessed in dextran sodium sulphate [DSS], IL-10(-/-), and T cell transfer colitis murine models. RNA sequencing of acidosis-activated TDAG8(-/-) and wildtype [WT] peritoneal macrophages [M Phi s] was performed. Results: mRNA expression of IFN-gamma, TNF, IL-6, and iNOS in TDAG8(-/-) mice increased significantly in colonic lymphoid patches and in colonic tissue in acute and chronic DSS colitis, respectively. In transfer colitis, there was a trend towards increased IFN-gamma, iNOS, and IL-6 expression in mice receiving TDAG8(-/-) T cells. However, absence of TDAG8 did not lead to changes in clinical scores in the models tested. Increased numbers of infiltrating M Phi s and neutrophils, but not CD3+ T cells, were observed in DSS-treated TDAG8(-/-) mice. No differences in infiltrating CD3+ T cells were observed between mice receiving TDAG8(-/-) or WT naive T cells in transfer colitis. RNA sequencing showed that acidosis activation of TDAG8 in M Phi s modulated the expression of immune response genes. Conclusions: TDAG8 deficiency triggers colonic M Phi and neutrophil infiltration, and expression of pro-inflammatory mediators in DSS colitis models. In transfer colitis, mice receiving TDAG8(-/-) T cells presented a significantly higher spleen weight and a tendency towards increased expression of pro-inflammatory markers of monocyte/M Phi activity. |
| Databáze: | OpenAIRE |
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