Journal of Neuroimmune Pharmacology

, Volume 13, Issue 3, pp 330–344 | Cite as

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 Buch


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.


HIV CNS Extracellular vesicles miR-9 PTEN 



We thank Dr. Changhai Tian, Shannon Callen and Blake Dallon for their outstanding technical assistance and insightful discussion. This work was supported by grants DA041751, DA043164, MH112848, DA040397, DA043138 (SB), and DA033150, DA042704 (GH) from the National Institutes of Health. The support by Nebraska Center for Substance Abuse Research is acknowledged. The project described was also supported by the NIH, National Institute of Mental Health, 2P30MH062261. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. This work was also supported by the National Natural Science Foundation of China (Grant No.81601125 to LY).

Compliance with Ethical Standards

Conflict of Interest

The authors declare no competing financial interests in relation to the work described.


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Lu Yang
    • 1
  • Fang Niu
    • 2
  • Honghong Yao
    • 3
    • 4
  • Ke Liao
    • 2
  • Xufeng Chen
    • 5
  • Yeonhee Kook
    • 2
  • Rong Ma
    • 6
  • Guoku Hu
    • 2
  • Shilpa Buch
    • 2
  1. 1.School of MedicineUniversity of Electronic Science and Technology of ChinaChengduChina
  2. 2.Department of Pharmacology and Experimental NeuroscienceUniversity of Nebraska Medical CenterOmahaUSA
  3. 3.Department of PharmacologyMedical School of Southeast University, Southeast UniversityNanjingChina
  4. 4.Key Laboratory of Developmental Genes and Human Disease, Southeast UniversityInstitute of Life SciencesNanjingChina
  5. 5.The first Affiliated Hospital of Nanjing Medical UniversityNanjingChina
  6. 6.Department of Pharmacology, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina

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