Lack of the pH-sensing Receptor TDAG8 [GPR65] in Macrophages Plays a Detrimental Role in Murine Models of Inflammatory Bowel Disease
Por:
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 and de Valliere, C
Publicada:
1 feb 2019
Resumen:
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.
Filiaciones:
Tcymbarevich, I:
Univ Zurich, Univ Zurich Hosp, Dept Gastroenterol & Hepatol, Ramistr 100, CH-8091 Zurich, Switzerland
Richards, S:
Novartis Inst Biomed Res, Basel, Switzerland
Russo, G:
Univ Zurich, ETH Zurich, Funct Genom Ctr Zurich, Zurich, Switzerland
Kuhn-Georgijevic, J:
Univ Zurich, ETH Zurich, Funct Genom Ctr Zurich, Zurich, Switzerland
:
Univ Zurich, Univ Zurich Hosp, Dept Gastroenterol & Hepatol, Ramistr 100, CH-8091 Zurich, Switzerland
Baebler, K:
Univ Zurich, Univ Zurich Hosp, Dept Gastroenterol & Hepatol, Ramistr 100, CH-8091 Zurich, Switzerland
Lang, S:
Univ Zurich, Univ Zurich Hosp, Dept Gastroenterol & Hepatol, Ramistr 100, CH-8091 Zurich, Switzerland
Bengs, S:
Univ Zurich, Univ Zurich Hosp, Dept Gastroenterol & Hepatol, Ramistr 100, CH-8091 Zurich, Switzerland
Atrott, K:
Univ Zurich, Univ Zurich Hosp, Dept Gastroenterol & Hepatol, Ramistr 100, CH-8091 Zurich, Switzerland
Bettoni, C:
Univ Zurich, Inst Physiol, Zurich, Switzerland
Gruber, S:
Univ Zurich, Univ Zurich Hosp, Dept Gastroenterol & Hepatol, Ramistr 100, CH-8091 Zurich, Switzerland
Univ Zurich, Inst Physiol, Zurich, Switzerland
Frey-Wagner, I:
Univ Zurich, Univ Zurich Hosp, Dept Gastroenterol & Hepatol, Ramistr 100, CH-8091 Zurich, Switzerland
Scharl, M:
Univ Zurich, Univ Zurich Hosp, Dept Gastroenterol & Hepatol, Ramistr 100, CH-8091 Zurich, Switzerland
Zurich Ctr Integrat Human Physiol, Zurich, Switzerland
Misselwitz, B:
Univ Zurich, Univ Zurich Hosp, Dept Gastroenterol & Hepatol, Ramistr 100, CH-8091 Zurich, Switzerland
Wagner, C:
Univ Zurich, Inst Physiol, Zurich, Switzerland
Zurich Ctr Integrat Human Physiol, Zurich, Switzerland
Seuwen, K:
Novartis Inst Biomed Res, Basel, Switzerland
Rogler, G:
Univ Zurich, Univ Zurich Hosp, Dept Gastroenterol & Hepatol, Ramistr 100, CH-8091 Zurich, Switzerland
Zurich Ctr Integrat Human Physiol, Zurich, Switzerland
Ruiz, P:
Univ Zurich, Univ Zurich Hosp, Dept Gastroenterol & Hepatol, Ramistr 100, CH-8091 Zurich, Switzerland
Spalinger, M:
Univ Zurich, Univ Zurich Hosp, Dept Gastroenterol & Hepatol, Ramistr 100, CH-8091 Zurich, Switzerland
de Valliere, C:
Univ Zurich, Univ Zurich Hosp, Dept Gastroenterol & Hepatol, Ramistr 100, CH-8091 Zurich, Switzerland
Bronze
|