Protective role of orphan G protein-coupled receptor GPR35 in the pathogenesis of colitis through regulating epithelial barrier function and immune responses

BACKGROUND AND OBJECTIVE: GPR35 is involved in the pathogenesis of colitis. However, because GPR35 is expressed in colonic epithelial and inflammatory/immune cells, its precise protective mechanisms remain unclear. We investigated the role of GPR35 in colitis, especially its relation to epithelial barrier function and inflammatory/immune responses. METHODS: We performed GPR35 knockout (KO) in a dextran sodium sulfate (DSS)-induced murine colitis model and elucidated the role of GPR35 through various experiments, including histological analysis, intestinal permeability, immunohistochemical staining, RT-qPCR, and western blotting. RESULTS: GPR35KO mice exhibited significantly exacerbated DSS-induced colitis, accompanied by upregulation of cytokines, compared with wild-type (WT) mice. An investigation using bone marrow (BM)-chimeric mice revealed that GPR35KO, which is expressed in both hematopoietic and non-hematopoietic cells, contributed to this exacerbation. GPR35KO mice showed significantly increased intestinal permeability compared with WT mice under normal conditions. Although no differences were observed in goblet cell number or epithelial proliferation between WT and GPR35KO mice, the expression levels of intercellular junction proteins were significantly lower in the normal colons of GPR35KO mice. Lipopolysaccharide-stimulated cytokine expression was significantly enhanced in BM-derived macrophages obtained from GPR35KO mice compared with WT mice. CONCLUSIONS: GPR35 contributes to colonic protection by regulating epithelial barrier function and inflammatory/immune responses.