CD226 deficiency on regulatory T cells aggravates renal fibrosis via up‐regulation of Th2 cytokines through miR‐340. Issue 4 (4th December 2019)

• Record Type: Journal Article
• Authors: Mu, Yang; Zhang, Jinxue; Liu, Yongming; Ma, Jingchang; Jiang, Dongxu; Zhang, Xuexin; Yi, Xin; Cheng, Kun; Shen, Shen; Yang, Yixin; Zhuang, Ran; Zhang, Yuan
• Is Part Of: Journal of leukocyte biology. Volume 107:Issue 4(2020)
• Page Start: 573
• Page End: 587
• Publication Date: 2019-12-04
• Subjects: CD226 -- microRNA -- renal fibrosis -- Th2 cell -- Treg -- unilateral ureteral obstruction; Leucocytes -- Periodicals; Reticulo-endothelial system -- Periodicals; 571.96
• DOI: 10.1002/JLB.2MA1119-174RR
• Languages: English
• ISSNs: 0741-5400

Abstract

Abstract: In this study, we observed that deletion of CD226 on regulatory T cells (Tregs) precedes renal fibrosis in a mouse unilateral ureteral obstruction (UUO) model. First, we generated Treg‐specific CD226 gene knockout mice (CD226 fl/fl Foxp3 YFP‐Cre ). Next, CD226 fl/fl Foxp3 YFP‐Cre mice and Foxp3 YFP‐Cre control mice were subjected to UUO surgery. Pathologic analysis and Sirius red and Masson's trichrome staining showed that the kidneys of CD226 fl/fl Foxp3 YFP‐Cre mice following UUO showed much more severe interstitial fibrosis than Foxp3 YFP‐Cre control mice at days 10 and 20. Additionally, CD226 fl/fl Foxp3 YFP‐Cre mice showed increased fibronectin expression, as demonstrated by immunohistochemistry (IHC) staining. Although Treg cell‐restricted CD226 deficiency showed increased Foxp3 + expression, expression of the cell surface functional molecule CD103 was significantly reduced, indicating impaired homeostasis in the Tregs of CD226 fl/fl Foxp3 YFP‐Cre mice. To better understand CD226 function, RNA sequencing (RNA‐Seq) analysis was conducted in Tregs isolated from CD226 fl/fl Foxp3 YFP‐Cre and Foxp3 YFP‐Cre mice. RNA‐Seq data showed that the helper T cell (Th) 2‐related cytokines IL‐4 and IL‐10 were significantly up‐regulated in CD226 deficient Tregs. In addition, mRNA analysis of kidney samples from the mice following UUO by qPCR also showed increased IL‐4 and IL‐10 expression in CD226 fl/fl Foxp3 YFP‐Cre mice, as well as elevated TGF‐β1 levels, indicating that CD226 deficiency in Tregs resulted in the acquisition of the ability to produce Th2 cytokines. Finally, we found that microRNA‐340 (miR‐340), which was down‐regulated in Tregs isolated from CD226 fl/fl Foxp3 YFP‐Cre mice, directly regulated IL‐4 gene expression in vitro. These data suggest that the promotion of CD226 signaling on Tregs is a therapeutic target for renal disease. Abstract : Immune co‐stimulatory CD226 in regulatory T cells plays a critical role in renal fibrosis in the mouse unilateral ureteral obstruction model.