title: MiR-125a targets effector programs to stabilize Treg-mediated immune homeostasis.
abstract: 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.
authors.affiliation: 1] State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China [2] Joint Molecular Rheumatology Laboratory of the Institute of Health Sciences and Shanghai Renji Hospital, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Shanghai Jiaotong University School of Medicine, Shanghai 200025, China [3] Department of Genetics, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Wen
authors.initials: W
authors.lastname: Pan
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Shu
authors.initials: S
authors.lastname: Zhu
authors.affiliation: 1] State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China [2] Joint Molecular Rheumatology Laboratory of the Institute of Health Sciences and Shanghai Renji Hospital, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
authors.forename: Dai
authors.initials: D
authors.lastname: Dai
authors.affiliation: MedImmune LLC, Gaithersburg, Maryland 20878, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200025, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.affiliation: Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200025, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Gagliani
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Yunjiang
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: 1] State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China [2] Joint Molecular Rheumatology Laboratory of the Institute of Health Sciences and Shanghai Renji Hospital, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
authors.forename: Yuanjia
authors.initials: Y
authors.lastname: Tang
authors.affiliation: Center for Autoimmune Genomics and Etiology (CAGE) and Divisions of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati Ohio 45229, USA.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Weirauch
authors.affiliation: School of Electronic and Computing Systems, University of Cincinnati, Cincinnati, Ohio 45221, USA.
authors.forename: Xiaoting
authors.initials: X
authors.lastname: Chen
authors.affiliation: MedImmune LLC, Gaithersburg, Maryland 20878, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: MedImmune LLC, Gaithersburg, Maryland 20878, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.affiliation: MedImmune LLC, Gaithersburg, Maryland 20878, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China.
authors.forename: Youcun
authors.initials: Y
authors.lastname: Qian
authors.affiliation: Division of Gastroenterology and Hepathology, Renji Hospital, Shanghai Institute of Digestive Disease, Shanghai Jiaotong University School of Medicine, Shanghai 200001, China.
authors.forename: Yingxuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Division of Gastroenterology and Hepathology, Renji Hospital, Shanghai Institute of Digestive Disease, Shanghai Jiaotong University School of Medicine, Shanghai 200001, China.
authors.forename: Jingyuan
authors.initials: J
authors.lastname: Fang
authors.affiliation: MedImmune LLC, Gaithersburg, Maryland 20878, USA.
authors.forename: Ronald
authors.initials: R
authors.lastname: Herbst
authors.affiliation: MedImmune LLC, Gaithersburg, Maryland 20878, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Richman
authors.affiliation: MedImmune LLC, Gaithersburg, Maryland 20878, USA.
authors.forename: Bahija
authors.initials: B
authors.lastname: Jallal
authors.affiliation: 1] Center for Autoimmune Genomics and Etiology (CAGE) and Divisions of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati Ohio 45229, USA [2] US Department of Veterans Affairs Medical Center, Cincinnati, Ohio 45220, USA.
authors.forename: John B
authors.initials: JB
authors.lastname: Harley
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.affiliation: MedImmune LLC, Gaithersburg, Maryland 20878, USA.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Yao
authors.affiliation: 1] State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200032, China [2] Joint Molecular Rheumatology Laboratory of the Institute of Health Sciences and Shanghai Renji Hospital, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, and Shanghai Jiaotong University School of Medicine, Shanghai 200025, China [3] Center for Autoimmune Genomics and Etiology (CAGE) and Divisions of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati Ohio 45229, USA [4] Collaborative Innovation Center of Systems Biomedicine, Shanghai Jiaotong University, Shanghai 200240, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Shen
mesh_terms: D000818:Animals; D016022:Case-Control Studies; D003092:Colitis / Q000378:metabolism / Q000473:pathology; D003424:Crohn Disease; D015536:Down-Regulation; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007111:Immunity, Cellular / Q000502:physiology*; D008180:Lupus Erythematosus, Systemic; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009444:Neuritis, Autoimmune, Experimental / Q000378:metabolism / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*
chemical_list: D018398:Homeodomain Proteins; C531888:MIRN125 microRNA, human; D035683:MicroRNAs; C527468:Mirn125 microRNA, mouse; C064658:RAG-1 protein