CD8 T Cell‐Derived Exosomal miR‐186‐5p Elicits Renal Inflammation via Activating Tubular TLR7/8 Signal Axis

Author:

Xu Xiaodong1ORCID,Qu Shuang2,Zhang Changming1,Zhang Mingchao1,Qin Weisong1,Ren Guisheng1,Bao Hao1,Li Limin2,Zen Ke3,Liu Zhihong1ORCID

Affiliation:

1. National Clinical Research Center of Kidney Diseases Jinling Hospital Nanjing University School of Medicine Nanjing Jiangsu 210002 China

2. School of Life Science and Technology China Pharmaceutical University 639 Longmian Avenue Nanjing Jiangsu 211198 China

3. State Key Laboratory of Pharmaceutical Biotechnology Nanjing University School of Life Sciences Nanjing Jiangsu 210093 China

Abstract

AbstractT cells play an important role in the development of focal segmental glomerulosclerosis (FSGS). The mechanism underlying such T cell‐based kidney disease, however, remains elusive. Here the authors report that activated CD8 T cells elicit renal inflammation and tissue injury via releasing miR‐186‐5p‐enriched exosomes. Continuing the cohort study identifying the correlation of plasma level of miR‐186‐5p with proteinuria in FSGS patients, it is demonstrated that circulating miR‐186‐5p is mainly derived from activated CD8 T cell exosomes. Renal miR‐186‐5p, which is markedly increased in FSGS patients and mice with adriamycin‐induced renal injury, is mainly delivered by CD8 T cell exosomes. Depleting miR‐186‐5p strongly attenuates adriamycin‐induced mouse renal injury. Supporting the function of exosomal miR‐186‐5p as a key circulating pathogenic factor, intravenous injection of miR‐186‐5p or miR‐186‐5p‐containing T cell exosomes results in mouse renal inflammation and tissue injury. Tracing the injected T cell exosomes shows their preferential distribution in mouse renal tubules, not glomerulus. Mechanistically, miR‐186‐5p directly activates renal tubular TLR7/8 signal and initiates tubular cell apoptosis. Mutating the TLR7‐binding sequence on miR‐186‐5p or deleting mouse TLR7 largely abolishes renal tubular injuries induced by miR‐186‐5p or adriamycin. These findings reveal a causative role of exosomal miR‐186‐5p in T cell‐mediated renal dysfunction.

Funder

National Key Research and Development Program of China

National Natural Science Foundation of China

China Postdoctoral Science Foundation

Publisher

Wiley

Subject

General Physics and Astronomy,General Engineering,Biochemistry, Genetics and Molecular Biology (miscellaneous),General Materials Science,General Chemical Engineering,Medicine (miscellaneous)

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