Wenjing Yang1, Han Liu2, Leiqi Xu2, Tianming Yu1, Xiaojing Zhao3, Suxia Yao1, Qihong Zhao4, Sean Barnes5, Steven M Cohn5, Sara M Dann6, Hongjie Zhang7, Xiuli Zuo8, Yanqing Li8, Yingzi Cong9. 1. Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas. 2. Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas; Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, China. 3. Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas; Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China. 4. Bristol Myers Squibb, Princeton, New Jersey. 5. Department of Gastroenterology and Hepatology, University of Texas Medical Branch at Galveston, Galveston, Texas. 6. Department of Internal Medicine, The University of Texas Medical Branch, Galveston, Texas. 7. Department of Gastroenterology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China. 8. Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, China. 9. Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas; Department of Pathology, The University of Texas Medical Branch, Galveston, Texas. Electronic address: yicong@utmb.edu.
Abstract
BACKGROUND & AIMS: G protein-coupled receptor (GPR) 120 has been implicated in regulating metabolic syndromes with anti-inflammatory function. However, the role of GPR120 in intestinal inflammation is unknown. Here, we investigated whether and how GPR120 regulates CD4+ T cell function to inhibit colitis development. METHODS: Dextran sodium sulfate (DSS)-induced colitis model, Citrobacter rodentium infection model, and CD4+ T cell adoptive transfer model were used to analyze the role of GPR120 in regulating colitis development. The effect of GPR120 on CD4+ T cell functions was analyzed by RNA sequencing, flow cytometry, and Seahorse metabolic assays. Mice were administered GPR120 agonist for investigating the potential of GPR120 agonist in preventing and treating colitis. RESULTS: Deficiency of GPR120 in CD4+ T cells resulted in more severe colitis in mice upon dextran sodium sulfate insult and enteric infection. Transfer of GPR120-deficient CD4+CD45Rbhi T cells induced more severe colitis in Rag-/- mice with lower intestinal interleukin (IL) 10+CD4+ T cells. Treatment with the GPR120 agonist CpdA promoted CD4+ T cell production of IL10 by up-regulating Blimp1 and enhancing glycolysis, which was regulated by mTOR. GPR120 agonist-treated wild-type, but not IL10-deficient and Blimp1-deficient, T helper 1 cells induced less severe colitis. Furthermore, oral administration of GPR120 agonist protected mice from intestinal inflammation in both prevention and treatment schemes. Gpr120 expression was positively correlated with Il10 expression in the human colonic mucosa, including patients with inflammatory bowel diseases. CONCLUSIONS: Our findings show the role of GPR120 in regulating intestinal CD4+ T cell production of IL10 to inhibit colitis development, which identifies GPR120 as a potential therapeutic target for treating inflammatory bowel diseases.
BACKGROUND & AIMS: G protein-coupled receptor (GPR) 120 has been implicated in regulating metabolic syndromes with anti-inflammatory function. However, the role of GPR120 in intestinal inflammation is unknown. Here, we investigated whether and how GPR120 regulates CD4+ T cell function to inhibit colitis development. METHODS: Dextran sodium sulfate (DSS)-induced colitis model, Citrobacter rodentium infection model, and CD4+ T cell adoptive transfer model were used to analyze the role of GPR120 in regulating colitis development. The effect of GPR120 on CD4+ T cell functions was analyzed by RNA sequencing, flow cytometry, and Seahorse metabolic assays. Mice were administered GPR120 agonist for investigating the potential of GPR120 agonist in preventing and treating colitis. RESULTS: Deficiency of GPR120 in CD4+ T cells resulted in more severe colitis in mice upon dextran sodium sulfate insult and enteric infection. Transfer of GPR120-deficient CD4+CD45Rbhi T cells induced more severe colitis in Rag-/- mice with lower intestinal interleukin (IL) 10+CD4+ T cells. Treatment with the GPR120 agonist CpdA promoted CD4+ T cell production of IL10 by up-regulating Blimp1 and enhancing glycolysis, which was regulated by mTOR. GPR120 agonist-treated wild-type, but not IL10-deficient and Blimp1-deficient, T helper 1 cells induced less severe colitis. Furthermore, oral administration of GPR120 agonist protected mice from intestinal inflammation in both prevention and treatment schemes. Gpr120 expression was positively correlated with Il10 expression in the human colonic mucosa, including patients with inflammatory bowel diseases. CONCLUSIONS: Our findings show the role of GPR120 in regulating intestinal CD4+ T cell production of IL10 to inhibit colitis development, which identifies GPR120 as a potential therapeutic target for treating inflammatory bowel diseases.
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