OGR1 (GPR68) and TDAG8 (GPR65) Have Antagonistic Effects in Models of Colonic Inflammation

Area of Science:

• Gastroenterology and Immunology
• Molecular and Cellular Biology

Background:

• G-protein-coupled receptors (GPRs) like ovarian cancer GPR1 (OGR1/GPR68) and T cell death-associated gene 8 (TDAG8/GPR65) are pH sensors implicated in inflammatory bowel disease (IBD).
• OGR1 and TDAG8 exhibit opposing roles in inflammation, necessitating an understanding of their predominant physiological relevance.

Purpose of the Study:

• To investigate the individual and combined roles of OGR1 and TDAG8 in murine models of intestinal inflammation.
• To determine the predominant receptor in mediating inflammatory responses and intestinal damage in IBD.

Main Methods:

• Utilized spontaneous and acute murine colitis models with targeted gene deletion of OGR1 and TDAG8.
• Assessed disease severity via clinical scoring and analyzed colonic tissue using quantitative polymerase chain reaction (qPCR) and flow cytometry (FACS).

Main Results:

• In acute colitis, OGR1 deficiency significantly reduced clinical scores, whereas TDAG8 deficiency or combined deficiency showed no significant difference from wildtype (WT).
• In spontaneous colitis, OGR1 deficiency decreased inflammation, while TDAG8 deficiency exacerbated it. Triple knockout mice showed reduced inflammation compared to TDAG8-deficient mice.
• Absence of OGR1 diminished pro-inflammatory cytokines in TDAG8-deficient mice and alleviated intestinal damage associated with TDAG8 deficiency, which was linked to increased IFNγ+ T-lymphocytes and IL-23 T-helper cells.

Conclusions:

• OGR1 plays a significant protective role in intestinal inflammation, counteracting the detrimental effects of TDAG8 deficiency.
• Both OGR1 and TDAG8 are identified as potential therapeutic targets for managing inflammatory bowel disease.