Lack of the pH-sensing Receptor TDAG8 [GPR65] in Macrophages Plays a Detrimental Role in Murine Models of Inflammatory Bowel Disease.

Abstract

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 wild-type [WT] peritoneal macrophages [MΦs] was performed.

RESULTS:

mRNA expression of IFN-γ, 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-γ, 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 MΦs 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 naïve T cells in transfer colitis. RNA sequencing showed that acidosis activation of TDAG8 in MΦs modulated the expression of immune response genes.

CONCLUSIONS:

TDAG8 deficiency triggers colonic MΦ 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/MΦ activity.

• Authors: Irina Tcymbarevich, Shola M Richards, Giancarlo Russo, Jelena Kühn-Georgijevic, Jesus Cosin-Roger, Katharina Baebler, Silvia Lang, Susan Bengs, Kirstin Atrott, Carla Bettoni, Sven Gruber, Isabelle Frey-Wagner, Michael Scharl, Benjamin Misselwitz, Carsten A Wagner, Klaus Seuwen, Gerhard Rogler, Pedro A Ruiz, Marianne Spalinger, Cheryl de Vallière
• Journal: Journal of Crohn's & colitis (J Crohns Colitis) Vol. 13 Issue 2 Pg. 245-258 (Feb 01 2019) ISSN: 1876-4479 [Electronic] England
• PMID: 30535144 (Publication Type: Journal Article)

Chemical References

• GPR65 protein, mouse
• Interleukin-6
• Receptors, G-Protein-Coupled
• Tumor Necrosis Factor-alpha
• Interferon-gamma
• Nitric Oxide Synthase Type II

Topics

• Animals
• Disease Models, Animal
• Inflammatory Bowel Diseases (metabolism, pathology)
• Interferon-gamma (metabolism)
• Interleukin-6
• Macrophages (metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Nitric Oxide Synthase Type II (metabolism)
• Receptors, G-Protein-Coupled (metabolism)
• Tumor Necrosis Factor-alpha (metabolism)