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

Abstract

CD4+ Tcells undergo immunometabolic activation to mount an immunogenic response during experimental autoimmune myocarditis (EAM). Exosomes are considered key messengers mediating multiple Tcell functions in autoimmune responses. However, the role of circulating exosomes in EAM immunopathogenesis and CD4+ Tcell 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+ Tcell 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 Tcell 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 invivo 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+ Tcell immunometabolic dysfunction and EAM pathogenesis via cargo miR-142.