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

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 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.

Keywords: CD4(+) T cells; T(H)1; T(H)17; Tripartite motif-containing 21; inflammatory bowel disease; mucosal inflammation.