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The TGF‐β/miR‐31/CEACAM1‐S axis inhibits CD4 + CD25 + Treg differentiation in systemic lupus erythematosus
Author(s) -
Liu Yanjuan,
Li Caiyan,
Yang Yang,
Li Tao,
Xu Yunfei,
Zhang Wenqin,
Li Muyuan,
Xiao Yizhi,
Hu Jie,
Liu Ke,
Li Quanzhen,
Gui Ming,
Zuo Xiaoxia,
Li Yisha,
Zhang Huali
Publication year - 2021
Publication title -
immunology and cell biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.999
H-Index - 104
eISSN - 1440-1711
pISSN - 0818-9641
DOI - 10.1111/imcb.12449
Subject(s) - il 2 receptor , downregulation and upregulation , gene knockdown , peripheral blood mononuclear cell , immunology , transforming growth factor , transforming growth factor beta , cancer research , immune system , chemistry , medicine , biology , apoptosis , in vitro , endocrinology , t cell , gene , biochemistry
Defects causing concomitant loss of CD25 expression in regulatory T cells (Tregs) have been identified in systemic lupus erythematosus (SLE). However, the cause of this deficiency is not fully understood. Carcinoembryonic antigen related cell adhesion molecule 1 (CEACAM1), an immune co‐receptor, contributes to general T‐cell function and activation. Our previous study revealed that CEACAM1 expression was upregulated in peripheral blood mononuclear cells (PBMCs) from patients with SLE. However, its role remains unclear. Herein, we confirmed CEACAM1, especially CEACAM1‐S, was upregulated in PBMCs from patients with SLE. CEACAM1‐S over‐expression inhibits CD4 + CD25 + Treg differentiation, whereas knockdown of CEACAM1 had the opposite effect in vitro . CEACAM1‐S is the target of miR‐31. MiR‐31 mimic inhibits CEACAM1 expression and enhances CD4 + CD25 + Treg differentiation, which was reversed by CEACAM1‐S over‐expression. Moreover, the circulating TGF‐β level was upregulated in SLE patients and TGF‐β reduced miR‐31 expression via enhancing NF‐κB activity. Importantly, CEACAM1 and TGF‐β mRNA levels were downregulated, while the miR‐31 level and the abundance of CD4 + CD25 + Tregs were increased in inactive patients compared with that in patients with active SLE. In addition, CEACAM1‐S expression was positively correlated with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, while CD4 + CD25 + Treg abundance and miR‐31 level were negatively correlated with the SLEDAI score. In conclusion, reduced activity of miR‐31 by TGF‐β, via the inhibition of NF‐ᴋB, acted to inhibit the differentiation of CD4 + CD25 + Tregs by directly targeting CEACAM1‐S and to promote autoimmunity.