MiR-125a targets effector programs to stabilize Treg-mediated immune homeostasis

• DOI: 10.1038/ncomms8096
• Publication Date: 2015-05-12T10:42:08Z
• Authors: Wen Pan; Shu Zhu; Dai Dai; Zheng Liu; Dan Li; Bin Li; Nicola Gagliani; Yunjiang Zheng; Yuanjia Tang; Matthew T. Weirauch; Xiaoting Chen; Wei Zhu; Yue Wang; Bo Chen; Youcun Qian; Yingxuan Chen; Jingyuan Fang; Ronald Herbst; Laura Richman; Bahija Jallal; John B. Harley; Richard A. Flavell; Yihong Yao; Nan Shen
• Keywords: Homeodomain Proteins; 0301 basic medicine; Immunity, Cellular; Down-Regulation; Colitis; Neuritis, Autoimmune, Experimental; T-Lymphocytes, Regulatory; 3. Good health; Mice, Inbred C57BL; Mice; MicroRNAs; 03 medical and health sciences; Crohn Disease; Case-Control Studies; Animals; Homeostasis; Humans; Lupus Erythematosus, Systemic

Although different autoimmune diseases show discrete clinical features, there are common molecular pathways intimately involved. Here we show that miR-125a is downregulated in peripheral CD4(+) T cells of human autoimmune diseases including systemic lupus erythematosus and Crohn's disease, and relevant autoimmune mouse models. miR-125a stabilizes both the commitment and immunoregulatory capacity of Treg cells. In miR-125a-deficient mice, the balance appears to shift from immune suppression to inflammation, and results in more severe pathogenesis of colitis and experimental autoimmune encephalomyelitis (EAE). The genome-wide target analysis reveals that miR-125a suppresses several effector T-cell factors including Stat3, Ifng and Il13. Using a chemically synthesized miR-125a analogue, we show potential to re-programme the immune homeostasis in EAE models. These findings point to miR-125a as a critical factor that controls autoimmune diseases by stabilizing Treg-mediated immune homeostasis.