Exosomal miR-9 Released from HIV Tat Stimulated Astrocytes Mediates Microglial Migration.

TitleExosomal miR-9 Released from HIV Tat Stimulated Astrocytes Mediates Microglial Migration.
Publication TypeJournal Article
Year of Publication2018
AuthorsYang, L, Niu, F, Yao, H, Liao, K, Chen, X, Kook, Y, Ma, R, Hu, G, Buch, S
JournalJ Neuroimmune Pharmacol
Date Published2018 09
Keywords3' Untranslated Regions, Aniline Compounds, Animals, Astrocytes, Benzylidene Compounds, Cell Line, Tumor, Cell Movement, Exosomes, HIV Infections, Humans, Mice, Mice, Inbred C57BL, Microglia, MicroRNAs, Neostriatum, PTEN Phosphohydrolase, tat Gene Products, Human Immunodeficiency Virus, Transfection

Chronic neuroinflammation still remains a common underlying feature of HIV-infected patients on combined anti-retroviral therapy (cART). Previous studies have reported that despite near complete suppression of virus replication by cART, cytotoxic viral proteins such as HIV trans-activating regulatory protein (Tat) continue to persist in tissues such as the brain and the lymph nodes, thereby contributing, in part, to chronic glial activation observed in HIV-associated neurological disorders (HAND). Understanding how the glial cells cross talk to mediate neuropathology is thus of paramount importance. MicroRNAs (miR) also known as regulators of gene expression, have emerged as key paracrine signaling mediators that regulate disease pathogenesis and cellular crosstalk, through their transfer via the extracellular vesicles (EV). In the current study we have identified a novel function of miR-9, that of mediating microglial migration. We demonstrate that miR-9 released from Tat-stimulated astrocytes can be taken up by microglia resulting in their migratory phenotype. Exposure of human astrocytoma (A172) cells to HIV Tat resulted in induction and release of miR-9 in the EVs, which, was taken up by microglia, leading in turn, increased migration of the latter cells, a process that could be blocked by both an exosome inhibitor GW4869 or a specific target protector of miR-9. Furthermore, it was also demonstrated that EV miR-9 mediated inhibition of the expression of target PTEN, via its binding to the 3'UTR seed sequence of the PTEN mRNA, was critical for microglial migration. To validate the role of miR-9 in this process, microglial cells were treated with EVs loaded with miR-9, which resulted in significant downregulation of PTEN expression with a concomitant increase in microglial migration. These findings were corroborated by transfecting microglia with a specific target protector of PTEN, that blocked miR-9-mediated downregulation of PTEN as well as microglial migration. In vivo studies wherein the miR-9 precursor-transduced microglia were transplanted into the striatum of mice, followed by assessing their migration in response to a stimulus administered distally, further validated the role of miR-9 in mediating microglial migration. Collectively, our findings provide evidence that glial crosstalk via miRs released from EVs play a vital role in mediating disease pathogenesis and could provide new avenues for development of novel therapeutic strategies aimed at dampening neuropathogenesis.

Alternate JournalJ Neuroimmune Pharmacol
PubMed ID29497921
PubMed Central IDPMC6082702
Grant ListR01 DA043138 / DA / NIDA NIH HHS / United States
R01 MH112848 / MH / NIMH NIH HHS / United States
R21 DA042704 / DA / NIDA NIH HHS / United States
P30 MH062261 / MH / NIMH NIH HHS / United States
U24 MH100928 / MH / NIMH NIH HHS / United States
R01 DA040397 / DA / NIDA NIH HHS / United States
R01 DA043164 / DA / NIDA NIH HHS / United States
R01 MH106425 / MH / NIMH NIH HHS / United States
R01 DA033150 / DA / NIDA NIH HHS / United States
R01 DA041751 / DA / NIDA NIH HHS / United States