2. Academic Validation
  3. Circulating Exosomes Control CD4+ T Cell Immunometabolic Functions via the Transfer of miR-142 as a Novel Mediator in Myocarditis

Circulating Exosomes Control CD4+ T Cell Immunometabolic Functions via the Transfer of miR-142 as a Novel Mediator in Myocarditis

  • Mol Ther. 2020 Dec 2;28(12):2605-2620. doi: 10.1016/j.ymthe.2020.08.015.
Ping Sun 1,  Naixin Wang 2,  Peng Zhao 3,  Chao Wang 1,  Hairu Li 1,  Qi Chen 2,  Ge Mang 2,  Weiwei Wang 2,  Shaohong Fang 4,  Guoqing Du 1,  Maomao Zhang 5,  Jiawei Tian 6
Affiliations

Affiliations

  • 1 Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China; The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang Province, China.
  • 2 The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang Province, China; Department of Cardiology, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
  • 3 Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China.
  • 4 The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang Province, China.
  • 5 The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Ministry of Education, Harbin, Heilongjiang Province, China; Department of Cardiology, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China. Electronic address: maomaolp1983@163.com.
  • 6 Department of Ultrasound, the Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China. Electronic address: jwtian2004@163.com.
PMID: 32882180 DOI: 10.1016/j.ymthe.2020.08.015
Abstract

CD4+ T cells undergo immunometabolic activation to mount an immunogenic response during experimental autoimmune myocarditis (EAM). Exosomes are considered key messengers mediating multiple T cell functions in autoimmune responses. However, the role of circulating exosomes in EAM immunopathogenesis and CD4+ T cell dysfunction remains elusive. Our objective was to elucidate the mechanism of action for circulating exosomes in EAM pathogenesis. We found that serum exosomes harvested from EAM mice induced CD4+ T cell immunometabolic dysfunction. Treatment with the exosome inhibitor GW4869 protected mice from developing EAM, underlying that exosomes are indispensable for the pathogenesis of EAM. Furthermore, by transfer of EAM exosomes, we confirmed that circulating exosomes initiate the T cell pathological immune response, driving the EAM pathological process. Mechanistically, EAM-circulating exosomes selectively loaded abundant MicroRNA (miR)-142. We confirmed methyl-CpG binding domain protein 2 (MBD2) and suppressor of cytokine signaling 1 (SOCS1) as functional target genes of miR-142. The miR-142/MBD2/MYC and miR-142/SOCS1 communication axes are critical to exosome-mediated immunometabolic turbulence. Moreover, the in vivo injection of the miR-142 inhibitor alleviated cardiac injury in EAM mice. This effect was abrogated by pretreatment with EAM exosomes. Collectively, our results indicate a newly endogenous mechanism whereby circulating exosomes regulate CD4+ T cell immunometabolic dysfunction and EAM pathogenesis via cargo miR-142.

Keywords

exosomes; experimental autoimmune myocarditis; glycolysis; miR-142.

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