Guangxi Zhou1, Wei Wu1, Lin Yu1, Tianming Yu1, Wenjing Yang1, Ping Wang2, Xiaoping Zhang3, Yingzi Cong4, Zhanju Liu5. 1. Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China. 2. Department of Central Laboratory, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China. 3. Institute of Intervention Vessel, Tongji University School of Medicine, Shanghai, China. Electronic address: zxpkxy@126.com. 4. Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Tex. Electronic address: yicong@utmb.edu. 5. Department of Gastroenterology, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China. Electronic address: liuzhanju88@126.com.
Abstract
BACKGROUND: Tripartite motif-containing (TRIM) 21 has been implicated in the pathogenesis of several types of autoimmune diseases. OBJECTIVE: We sought to elucidate TRIM21 expression in patients with inflammatory bowel diseases (IBDs) and its role in regulating intestinal mucosal inflammation. METHODS: TRIM21 expression was analyzed in the inflamed mucosa of patients with IBDs by means of quantitative RT-PCR and immunohistochemistry. Peripheral blood CD4+ T cells were transfected with lentivirus-expressing TRIM21 (LV-TRIM21) or LV-sh-TRIM21, and cytokine expression was determined by using quantitative RT-PCR and ELISA. TRIM21-/- mice were generated, and trinitrobenzene sulfonic acid- and CD45RBhighCD4+ T cell-induced colitis models were established to determine its role in induction of intestinal inflammation. RESULTS: TRIM21 was expressed predominantly in CD4+ T cells and decreased markedly in the inflamed mucosa of patients with IBDs compared with healthy control subjects. Ectopic expression of TRIM21 inhibited IBD CD4+ T cells to differentiate into TH1 and TH17 cells, whereas downregulation of TRIM21 had the opposite effects. TRIM21-/- mice had more severe colitis after administration of trinitrobenzene sulfonic acid compared with wild-type mice, which was characterized by increased expression of IFN-γ, TNF-α, and IL-17A in the colon. TRIM21-/-CD45RBhighCD4+ T cells reconstituted into recombination-activating gene (Rag1)-/- mice induced more severe colitis than in wild-type control mice. Mechanistically, interferon regulatory factor 3 was identified as a functional downstream target of TRIM21 in that silencing of interferon regulatory factor 3 suppressed TRIM21-/-CD4+ T-cell differentiation into TH1 and TH17 cells. CONCLUSIONS: TRIM21 plays a protective role in mucosal inflammation through inhibiting TH1 and TH17 cell differentiation. Thus TRIM21 might serve as a potential therapeutic target for the treatment of IBDs.
BACKGROUND:Tripartite motif-containing (TRIM) 21 has been implicated in the pathogenesis of several types of autoimmune diseases. OBJECTIVE: We sought to elucidate TRIM21 expression in patients with inflammatory bowel diseases (IBDs) and its role in regulating intestinal mucosal inflammation. METHODS:TRIM21 expression was analyzed in the inflamed mucosa of patients with IBDs by means of quantitative RT-PCR and immunohistochemistry. Peripheral blood CD4+ T cells were transfected with lentivirus-expressing TRIM21 (LV-TRIM21) or LV-sh-TRIM21, and cytokine expression was determined by using quantitative RT-PCR and ELISA. TRIM21-/- mice were generated, and trinitrobenzene sulfonic acid- and CD45RBhighCD4+ T cell-induced colitis models were established to determine its role in induction of intestinal inflammation. RESULTS:TRIM21 was expressed predominantly in CD4+ T cells and decreased markedly in the inflamed mucosa of patients with IBDs compared with healthy control subjects. Ectopic expression of TRIM21 inhibited IBD CD4+ T cells to differentiate into TH1 and TH17 cells, whereas downregulation of TRIM21 had the opposite effects. TRIM21-/- mice had more severe colitis after administration of trinitrobenzene sulfonic acid compared with wild-type mice, which was characterized by increased expression of IFN-γ, TNF-α, and IL-17A in the colon. TRIM21-/-CD45RBhighCD4+ T cells reconstituted into recombination-activating gene (Rag1)-/- mice induced more severe colitis than in wild-type control mice. Mechanistically, interferon regulatory factor 3 was identified as a functional downstream target of TRIM21 in that silencing of interferon regulatory factor 3 suppressed TRIM21-/-CD4+ T-cell differentiation into TH1 and TH17 cells. CONCLUSIONS:TRIM21 plays a protective role in mucosal inflammation through inhibiting TH1 and TH17 cell differentiation. Thus TRIM21 might serve as a potential therapeutic target for the treatment of IBDs.
Authors: Jonathan J Cho; Zhiwei Xu; Upasana Parthasarathy; Theodore T Drashansky; Eric Y Helm; Ashley N Zuniga; Kyle J Lorentsen; Samira Mansouri; Joshua Y Cho; Mariola J Edelmann; Duc M Duong; Torben Gehring; Thomas Seeholzer; Daniel Krappmann; Mohammad N Uddin; Danielle Califano; Rejean L Wang; Lei Jin; Hongmin Li; Dongwen Lv; Daohong Zhou; Liang Zhou; Dorina Avram Journal: Nat Commun Date: 2019-02-11 Impact factor: 14.919
Authors: Spyridon Megremis; Thomas D J Walker; Xiaotong He; James O'Sullivan; William E R Ollier; Hector Chinoy; Neil Pendleton; Antony Payton; Lynne Hampson; Ian Hampson; Janine A Lamb Journal: Commun Biol Date: 2021-03-26