Tripartite motif-containing (TRIM) 21 negatively regulates intestinal mucosal inflammation through inhibiting TH1/TH17 cell differentiation in patients with inflammatory bowel diseases

Publication date: October 2018

Source: Journal of Allergy and Clinical Immunology, Volume 142, Issue 4

Author(s): Guangxi Zhou, Wei Wu, Lin Yu, Tianming Yu, Wenjing Yang, Ping Wang, Xiaoping Zhang, Yingzi Cong, Zhanju Liu

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 CD45RB^highCD4⁺ 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 T_H1 and T_H17 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^−/−CD45RB^highCD4⁺ 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 T_H1 and T_H17 cells.

Conclusions

TRIM21 plays a protective role in mucosal inflammation through inhibiting T_H1 and T_H17 cell differentiation. Thus TRIM21 might serve as a potential therapeutic target for the treatment of IBDs.

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