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

Abstract

T 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.

Longitudinal change of serum exosomal miR-186-5p estimates major adverse cardiac events in acute myocardial infarction patients receiving percutaneous coronary intervention

“…Secondly, serum exosomal miR-186-5p was positively correlated with Scr and inversely linked with eGFR in AMI patients receiving PCI. It would be due to the fact that exosomal miR-186-5p might modulate Smad5 and toll-like receptor 7/8 axis to induce renal inflammation and fibrosis, which impaired renal function and resulted in a higher Scr and lower eGFR ( 24 , 25 ). Thirdly, serum exosomal miR-186-5p was positively related to CRP in AMI patients receiving PCI.…”

Different origin-derived exosomes and their clinical advantages in cancer therapy

“…found that miR-186–5p in CD8 T cell-derived exosomes caused renal inflammation and tissue damage. miR-186–5p directly activates TLR7/8 signaling axis in renal tubules to cause renal inflammation, which reveals the specific pathogenic mechanism and reason of the pathogenic role in T cell-mediated renal dysfunction and provides new ideas for the treatment of nephropathy ( 311 ). T cell-derived exosomes are still in the exploratory stage, and continuous efforts are still needed to achieve clinical transformation.…”