Abstract
Recent studies have found that extracellular vesicles (EVs) play an important role in normal and disease processes. In the present study, we 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. Indeed miR-21 in EV activates TLR7 in a reporter cell line, and the neurotoxicity is dependent upon TLR7, as neurons isolated from TLR7-/- knockout mice are protected from neurotoxicity. Further, we show that EVs isolated from the brains of monkeys with SIV induced CNS disease activates TLR7 and were neurotoxic when compared to EVs from control animals. Finally, we show 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.
Highlights
HIV-associated neurocognitive disorder (HAND) is a central nervous system (CNS) associated neurological disease where neurodegeneration is a consequence of CNS inflammation
Using a nonhuman primate model of HAND, simian immunodeficiency virus encephalitis (SIVE), we find that exosomes isolated from SIVE brains contain,microRNAs, including miR-21, that can serve as ligands to the key immune regulatory receptors, toll-like receptors, and can elicit neurotoxicity
We find that miR-21 is increased in extracellular vesicles (EVs) during SIVE pathogenesis and that it is deleterious to neurons by activating TLR7 dependent downstream cell death pathways
Summary
HIV-associated neurocognitive disorder (HAND) is a central nervous system (CNS) associated neurological disease where neurodegeneration is a consequence of CNS inflammation. The pathological characteristics of the most extreme form of this disease include astrogliosis, microgliosis, presence of multinucleated giant cells, and loss of dendrites and synapses [1,2,3], collectively termed HIV encephalitis (HIVE) These features are recapitulated in its nonhuman primate equivalent rhesus macaque model, simian immunodeficiency virus encephalitis (SIVE) [4]. Others and we identified that SIV/HIV infection upregulated microRNAs (miRNAs) in macaque and human brains [9,10,11] These studies have shown that upregulation of miRNAs can lead to neuronal dysfunction by targeting crucial genes and by repressing their expression in the CNS. EVs have been repeatedly discussed as potential carriers in the dissemination of disease pathology in neurodegenerative disorders, as they harbor proteins and RNA that can be transferred from the originating cell to a target cell [24]
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