TRIM21 negatively regulates intestinal mucosal inflammation through inhibiting Th1/Th17 cell differentiation in inflammatory bowel diseases

Publication date: Available online 4 November 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Guangxi Zhou, Wei Wu, Lin Yu, Tianming Yu, Wenjing Yang, Ping Wang, Xiaoping Zhang, Yingzi Cong, Zhanju Liu
BackgroundTripartite motif-containing (TRIM)21 has been implicated in pathogenesis of several types of autoimmune diseases.ObjectiveWe sought to elucidate expression of TRIM21 in patients with inflammatory bowel disease (IBD) and its role in regulating intestinal mucosal inflammation.MethodsTRIM21 expression was analyzed in inflamed mucosa of IBD patients by qRT-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 qRT-PCR and ELISA. TRIM21^−/− mice were generated, and trinitrobenzene sulphonic acid (TNBS)- and CD45RB^highCD4⁺ T cell-induced colitis models were established to determine its role in the induction of intestinal inflammation.ResultsTRIM21 was predominantly expressed in CD4⁺ T cells and markedly decreased in inflamed mucosa of IBD patients compared with healthy controls. Ectopic expression of TRIM21 inhibited IBD CD4⁺ T cells to differentiate into T helper (Th)1 and Th17 cells, whereas downregulation of TRIM21 had opposite effects. TRIM21^−/− mice developed more severe colitis following administration of TNBS compared with wild-type mice, characterized by increased expression of IFN-γ, TNF-α, and IL-17A in the colon. TRIM21^−/− CD45RB^highCD4⁺ T cells reconstituted into Rag-1^−/− mice induced more severe colitis than wild-type controls. Mechanistically, IRF3 was identified as a functional downstream target of TRIM21, in that silencing of IRF3 suppressed TRIM21^−/−CD4⁺ T cell differentiation into Th1 and Th17 cells.ConclusionsTRIM21 plays a protective role in mucosal inflammation through inhibiting Th1 and Th17 cell differentiation. Thus, TRIM21 may serve as a potential therapeutic target for treatment of IBD.

Teaser

●TRIM21 is decreased in inflamed mucosa of patients with active IBD and plays a protective role in mucosal inflammation through inhibiting Th1 and Th17 cell differentiation. TRIM21 may serve as a potential therapeutic target for treatment of IBD.


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