The TGF‐β/miR‐31/CEACAM1‐S axis inhibits CD4+CD25+ Treg differentiation in systemic lupus erythematosus. Issue 7 (4th May 2021)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Immunology and cell biology. Volume 99:Issue 7(2021)
• Page Start: 697
• Page End: 710
• Publication Date: 2021-05-04
• Subjects: CEACAM1‐S -- miR‐31 -- NF‐κB -- systemic lupus erythematous -- Treg; Immunology -- Periodicals; Cytology -- Periodicals; 616.079
• DOI: 10.1111/imcb.12449
• Languages: English
• ISSNs: 0818-9641

Abstract

Abstract: 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. Abstract : This study found that the circulating TGF‐β level was increased in sera from patients with systemic lupus erythematosus (SLE), and increased TGF‐β inhibits the activity of NF‐ᴋB, which leads to downregulation of miR‐31. Decreased MiR‐31 thereby promotes the post‐translational regulation of CEACAM1‐S, and subsequently increases CEACAM1‐S expression. Increased expression of CEACAM1‐S attenuates CD4 + CD25 + Treg cell differentiation, which is an important Treg phenotype that assists in controlling the pathogenicity of SLE.