The TGF-β/miR-31/CEACAM1-S axis inhibits CD4+CD25+ Treg differentiation in systemic lupus erythematosus,Immunology and Cell Biology

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The TGF-β/miR-31/CEACAM1-S axis inhibits CD4+CD25+ Treg differentiation in systemic lupus erythematosus
Immunology and Cell Biology ( IF 3.2 ) Pub Date : 2021-03-02 , DOI: 10.1111/imcb.12449
Yanjuan Liu _{1,

2,

3} , Caiyan Li _{1,

2} , Yang Yang _{1,

2} , Tao Li _{1,

2} , Yunfei Xu _{1,

2} , Wenqin Zhang _{1,

2} , Muyuan Li _{1,

2} , Yizhi Xiao ₁ , Jie Hu ₂ , Ke Liu ₂ , Quanzhen Li _{1,

4} , Ming Gui ₅ , Xiaoxia Zuo ₁ , Yisha Li ₁ , Huali Zhang _{1,

2,

6}

Affiliation

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.

中文翻译：

TGF-β/miR-31/CEACAM1-S 轴抑制系统性红斑狼疮的 CD4+CD25+Treg 分化

已在系统性红斑狼疮 (SLE) 中鉴定出导致调节性 T 细胞 (Treg) 中 CD25 表达随之丧失的缺陷。然而，这种缺陷的原因尚不完全清楚。癌胚抗原相关细胞粘附分子 1 (CEACAM1) 是一种免疫共受体，有助于一般 T 细胞功能和激活。我们之前的研究表明，SLE 患者的外周血单核细胞 (PBMC) 中 CEACAM1 表达上调。然而，它的作用仍不清楚。在此，我们证实 CEACAM1，尤其是 CEACAM1-S，在 SLE 患者的 PBMC 中上调。CEACAM1-S 过表达抑制 CD4 ⁺ CD25 ⁺ Treg 分化，而 CEACAM1 的敲低在体外具有相反的效果. CEACAM1-S 是 miR-31 的靶标。MiR-31 模拟物抑制 CEACAM1 表达并增强 CD4 ⁺ CD25 ⁺ Treg 分化，这被 CEACAM1-S 过表达逆转。此外，SLE 患者的循环 TGF-β 水平上调，TGF-β 通过增强 NF-κB 活性降低 miR-31 表达。重要的是，与活动性 SLE 患者相比，非活动性患者的CEACAM1 和 TGF-β mRNA 水平下调，而 miR-31 水平和 CD4 ⁺ CD25 ⁺ Tregs的丰度增加。此外，CEACAM1-S的表达与系统性红斑狼疮疾病活动指数（SLEDAI）评分呈正相关，而CD4 ⁺ CD25 ⁺Treg 丰度和 miR-31 水平与 SLEDAI 评分呈负相关。总之，TGF-β 通过抑制 NF-ᴋB 降低 miR-31 的活性，通过直接靶向 CEACAM1-S来抑制 CD4 ⁺ CD25 ⁺ Tregs的分化并促进自身免疫。

更新日期：2021-03-02

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