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

Lu Yang, Fang Niu, Honghong Yao, Ke Liao, Xufeng Chen, Yeonhee Kook, Rong Ma, Guoku Hu, Shilpa J Buch

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)330-344
Number of pages15
JournalJournal of Neuroimmune Pharmacology
Volume13
Issue number3
DOIs
StatePublished - Sep 1 2018

Fingerprint

MicroRNAs
Astrocytes
HIV
Microglia
Neuroglia
Down-Regulation
Paracrine Communication
tat Gene Products
Exosomes
Astrocytoma
Viral Proteins
Regulator Genes
Virus Replication
Nervous System Diseases
Cell Movement
Seeds
Therapeutics
Lymph Nodes
Phenotype
Gene Expression

Keywords

  • CNS
  • Extracellular vesicles
  • HIV
  • PTEN
  • miR-9

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Immunology and Allergy
  • Immunology
  • Pharmacology

Cite this

Exosomal miR-9 Released from HIV Tat Stimulated Astrocytes Mediates Microglial Migration. / Yang, Lu; Niu, Fang; Yao, Honghong; Liao, Ke; Chen, Xufeng; Kook, Yeonhee; Ma, Rong; Hu, Guoku; Buch, Shilpa J.

In: Journal of Neuroimmune Pharmacology, Vol. 13, No. 3, 01.09.2018, p. 330-344.

Research output: Contribution to journalArticle

Yang, Lu ; Niu, Fang ; Yao, Honghong ; Liao, Ke ; Chen, Xufeng ; Kook, Yeonhee ; Ma, Rong ; Hu, Guoku ; Buch, Shilpa J. / Exosomal miR-9 Released from HIV Tat Stimulated Astrocytes Mediates Microglial Migration. In: Journal of Neuroimmune Pharmacology. 2018 ; Vol. 13, No. 3. pp. 330-344.
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