Extracellular miR-21 Shown to Lead to Neurotoxicity in SIV Neurological Disease

Recent studies have found that extracellular vesicles (EVs) play an important role in normal and disease processes. In their recent study, a team of scientists led by researchers from the University of Nebraska Medical Center isolated and characterized EVs from the brains of rhesus macaques, both with and without simian immunodeficiency virus (SIV) induced central nervous system (CNS) disease.

Small RNA sequencing revealed increased miR-21 levels in EVs from SIV encephalitic (SIVE) brains. In situ hybridization revealed increased miR-21 expression in neurons and macrophage/microglial cells/nodules during SIV induced CNS disease. In vitro culture of macrophages revealed that miR-21 is released into EVs and is neurotoxic when compared to EVs derived from miR-21-/- knockout animals. A mutation of the sequence within miR-21, predicted to bind TLR7, eliminates this neurotoxicity. They further showed that EVs isolated from the brains of monkeys with SIV induced CNS disease activated TLR7 and were neurotoxic when compared to EVs from control animals. Finally, researchers showed that EV-miR-21 induced neurotoxicity was unaffected by apoptosis inhibition but could be prevented by a necroptosis inhibitor, necrostatin-1, highlighting the actions of this pathway in a growing number of CNS disorders.

Isolation and characterization of brain derived EVs. (A) Left, Electron microscopic (TEM) morphological analysis of EVs derived from uninfected (control) macaque brain.  (B) Small RNA sequencing performed on RNA isolated from uninfected, SIV and SIVE brains. Analysis revealed significantly increased expression of miR-21-5p, miR-100-5p and miR-146-5p, and decreased expression miR-126-5p, in SIVE. Error bars = SEM (C) qRT-PCR validation of miR-21 expression in EVs.