Journal
DIGESTIVE DISEASES AND SCIENCES
Volume 63, Issue 11, Pages 2910-2922Publisher
SPRINGER
DOI: 10.1007/s10620-018-5216-z
Keywords
G protein-coupled receptor 35; Inflammatory bowel disease; Colitis; Dextran sulfate sodium; Colon inflammation
Categories
Funding
- American Heart Association Scientist Development [13SDG16930098]
- NIH/NIDDK [R01 DK109036]
- Wayne State University Faculty Start-up Fund
- NIH/NHLBI [R01 HL128647]
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BackgroundG protein-coupled receptor 35 (GPR35) is an orphan receptor and is vastly expressed in immune cells and gastrointestinal cells, suggesting the potential physiological importance of GPR35 in these cells. Here, we tested the hypothesis that the lack of GPR35 expression in the colon mucosa exacerbates the severity of dextran sulfate sodium (DSS)-induced experimental colitis in mice.MethodsColitis was induced in GPR35 wild-type (GPR35(+/+)) and GPR35 knockout (GPR35(-/-)) mice through the administration of DSS in drinking water for 5days followed by regular facility water for 1day. Induction of colitis was evaluated by measuring relative body weight loss, clinical illness scores, and morphological changes in the colon. Abolition of Gpr35 gene expression in the colon mucosa of GPR35(-/-) mice was confirmed by quantitative real-time PCR (qPCR). Gene expressions of inflammatory and tissue remodeling cytokines were detected by qPCR. Human colorectal epithelial Caco cells were transfected with siRNA against GPR35 before treated with 1% DSS in vitro. Protein expressions were measured using Western blot.ResultsGPR35(-/-) mice receiving DSS showed a significantly worsened colitis disease with profound loss of body weight and a considerable amount of severe clinical illness compared to GPR35(+/+) mice that received DSS. The histology of colon sections from GPR35(-/-) mice showed extensive pathological changes including submucosal edema, diffuse ulcerations, and evidence of complete loss of crypts compared to wild-type mice. The mean histopathological score was significantly higher in GPR35(-/-) mice as compared to GPR35(+/+) mice. The qPCR data revealed significant expression of pro-inflammatory and tissue remodeling cytokines in GPR35(-/-) colon mucosa, including IL-1, CXCL1, CXCL2, CCL2, HMGB1, TGF1, TGF3, MMP1/9/12. The protein expressions of Zonula occludens-1, E-cadherin, Claudin1 were decreased upon knocking down GPR35 with or without 1% DSS treatment.ConclusionsOur experimental data suggest that lack of GPR35 resulted in worsened disease outcome in DSS-induced experimental colitis, indicating that GPR35 could play a crucial role in protecting from colonic inflammation and serve as a therapeutic target.
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