Advertisement

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
ORIGINAL ARTICLE

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.

Keywords

HIV CNS Extracellular vesicles miR-9 PTEN 

Notes

Acknowledgements

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.

References

  1. Alexander M, Ramstead AG, Bauer KM, Lee SH, Runtsch MC, Wallace J, Huffaker TB, Larsen DK, Tolmachova T, Seabra MC, Round JL, Ward DM, O'Connell RM (2017) Rab27-dependent exosome production inhibits chronic inflammation and enables acute responses to inflammatory stimuli. J Immunol 199:3559–3570.  https://doi.org/10.4049/jimmunol.1700904 CrossRefPubMedGoogle Scholar
  2. Andras IE, Leda A, Contreras MG, Bertrand L, Park M, Skowronska M, Toborek M (2017) Extracellular vesicles of the blood-brain barrier: role in the HIV-1 associated amyloid beta pathology. Mol Cell Neurosci 79:12–22CrossRefPubMedGoogle Scholar
  3. Basso M, Bonetto V (2016) Extracellular vesicles and a novel form of communication in the brain. Front Neurosci 10:127CrossRefPubMedPubMedCentralGoogle Scholar
  4. Bellingham SA, Hill AF (2017) Analysis of miRNA signatures in neurodegenerative prion disease. Methods Mol Biol 1658:67–80CrossRefPubMedGoogle Scholar
  5. Bethel-Brown C, Yao H, Callen S, Lee YH, Dash PK, Kumar A, Buch S (2011) HIV-1 tat-mediated induction of platelet-derived growth factor in astrocytes: role of early growth response gene 1. J Immunol 186:4119–4129CrossRefPubMedPubMedCentralGoogle Scholar
  6. Bokhari SM, Hegde R, Callen S, Yao H, Adany I, Li Q, Li Z, Pinson D, Yeh HW, Cheney PD, Buch S (2011) Morphine potentiates neuropathogenesis of SIV infection in rhesus macaques. J NeuroImmune Pharmacol 6:626–639CrossRefPubMedPubMedCentralGoogle Scholar
  7. Booth AM, Fang Y, Fallon JK, Yang JM, Hildreth JE, Gould SJ (2006) Exosomes and HIV gag bud from endosome-like domains of the T cell plasma membrane. J Cell Biol 172:923–935CrossRefPubMedPubMedCentralGoogle Scholar
  8. Burda JE, Bernstein AM, Sofroniew MV (2016) Astrocyte roles in traumatic brain injury. Exp Neurol 275(Pt 3):305–315CrossRefPubMedGoogle Scholar
  9. Cai Y, Yang L, Callen S, Buch S (2016) Multiple faceted roles of cocaine in potentiation of HAND. Curr HIV Res 14:412–416CrossRefPubMedGoogle Scholar
  10. Chaudhuri AD, Yelamanchili SV, Marcondes MC, Fox HS (2013) Up-regulation of microRNA-142 in simian immunodeficiency virus encephalitis leads to repression of sirtuin1. FASEB J 27:3720–3729CrossRefPubMedPubMedCentralGoogle Scholar
  11. Chauhan A, Hahn S, Gartner S, Pardo CA, Netesan SK, McArthur J, Nath A (2007) Molecular programming of endothelin-1 in HIV-infected brain: role of tat in up-regulation of ET-1 and its inhibition by statins. FASEB J 21:777–789CrossRefPubMedGoogle Scholar
  12. Chivero ET, Guo ML, Periyasamy P, Liao K, Callen SE, Buch S (2017) HIV-1 tat primes and activates microglial NLRP3 Inflammasome-mediated Neuroinflammation. J Neurosci 37:3599–3609CrossRefPubMedPubMedCentralGoogle Scholar
  13. Chugh P, Fan S, Planelles V, Maggirwar SB, Dewhurst S, Kim B (2007) Infection of human immunodeficiency virus and intracellular viral tat protein exert a pro-survival effect in a human microglial cell line. J Mol Biol 366:67–81CrossRefPubMedGoogle Scholar
  14. Dickens AM, Tovar YRLB, Yoo SW, Trout AL, Bae M, Kanmogne M, Megra B, Williams DW, Witwer KW, Gacias M, Tabatadze N, Cole RN, Casaccia P, Berman JW, Anthony DC, Haughey NJ (2017) Astrocyte-shed extracellular vesicles regulate the peripheral leukocyte response to inflammatory brain lesions. Sci Signal 10(473):eaai7696Google Scholar
  15. El-Hage N, Podhaizer EM, Sturgill J, Hauser KF (2011) Toll-like receptor expression and activation in astroglia: differential regulation by HIV-1 tat, gp120, and morphine. Immunol Investig 40:498–522CrossRefGoogle Scholar
  16. Endersby R, Baker SJ (2008) PTEN signaling in brain: neuropathology and tumorigenesis. Oncogene 27:5416–5430CrossRefPubMedGoogle Scholar
  17. Fan Y, He JJ (2016) HIV-1 tat induces unfolded protein response and endoplasmic reticulum stress in astrocytes and causes neurotoxicity through glial fibrillary acidic protein (GFAP) activation and aggregation. J Biol Chem 291:22819–22829CrossRefPubMedPubMedCentralGoogle Scholar
  18. Fang Y, Wu N, Gan X, Yan W, Morrell JC, Gould SJ (2007) Higher-order oligomerization targets plasma membrane proteins and HIV gag to exosomes. PLoS Biol 5:e158CrossRefPubMedPubMedCentralGoogle Scholar
  19. Gray F, Chretien F, Vallat-Decouvelaere AV, Scaravilli F (2003) The changing pattern of HIV neuropathology in the HAART era. J Neuropathol Exp Neurol 62:429–440CrossRefPubMedGoogle Scholar
  20. Henderson LJ, Sharma A, Monaco MC, Major EO, Al-Harthi L (2012) Human immunodeficiency virus type 1 (HIV-1) transactivator of transcription through its intact core and cysteine-rich domains inhibits Wnt/beta-catenin signaling in astrocytes: relevance to HIV neuropathogenesis. J Neurosci 32:16306–16313CrossRefPubMedPubMedCentralGoogle Scholar
  21. Hu G, Drescher KM, Chen XM (2012a) Exosomal miRNAs: biological properties and therapeutic potential. Front Genet 3:56PubMedPubMedCentralGoogle Scholar
  22. Hu G, Yao H, Chaudhuri AD, Duan M, Yelamanchili SV, Wen H, Cheney PD, Fox HS, Buch S (2012b) Exosome-mediated shuttling of microRNA-29 regulates HIV tat and morphine-mediated neuronal dysfunction. Cell Death Dis 3:e381CrossRefPubMedPubMedCentralGoogle Scholar
  23. Hu G, Gong AY, Roth AL, Huang BQ, Ward HD, Zhu G, Larusso NF, Hanson ND, Chen XM (2013) Release of luminal exosomes contributes to TLR4-mediated epithelial antimicrobial defense. PLoS Pathog 9:e1003261CrossRefPubMedPubMedCentralGoogle Scholar
  24. Hu G, Yang L, Cai Y, Niu F, Mezzacappa F, Callen S, Fox HS, Buch S (2016) Emerging roles of extracellular vesicles in neurodegenerative disorders: focus on HIV-associated neurological complications. Cell Death Dis 7:e2481CrossRefPubMedPubMedCentralGoogle Scholar
  25. Hu G, Liao K, Yang L, Pendyala G, Kook Y, Fox HS, Buch S (2017) Tat-mediated induction of miRs-34a & -138 promotes astrocytic activation via downregulation of SIRT1: implications for aging in HAND. J NeuroImmune Pharmacol 12:420–432CrossRefPubMedGoogle Scholar
  26. Jaworski E, Saifuddin M, Sampey G, Shafagati N, Van Duyne R, Iordanskiy S, Kehn-Hall K, Liotta L, Petricoin E 3rd, Young M, Lepene B, Kashanchi F (2014) The use of Nanotrap particles technology in capturing HIV-1 virions and viral proteins from infected cells. PLoS One 9:e96778CrossRefPubMedPubMedCentralGoogle Scholar
  27. Jensen K, Bikas A, Patel A, Kushchayeva Y, Costello J, McDaniel D, Burman K, Vasko V (2017) Nelfinavir inhibits proliferation and induces DNA damage in thyroid cancer cells. Endocr Relat Cancer 24:147–156CrossRefPubMedGoogle Scholar
  28. Kadiu I, Narayanasamy P, Dash PK, Zhang W, Gendelman HE (2012) Biochemical and biologic characterization of exosomes and microvesicles as facilitators of HIV-1 infection in macrophages. J Immunol 189:744–754CrossRefPubMedPubMedCentralGoogle Scholar
  29. Kurose K, Gilley K, Matsumoto S, Watson PH, Zhou XP, Eng C (2002) Frequent somatic mutations in PTEN and TP53 are mutually exclusive in the stroma of breast carcinomas. Nat Genet 32:355–357CrossRefPubMedGoogle Scholar
  30. Langford D, Masliah E (2001) Crosstalk between components of the blood brain barrier and cells of the CNS in microglial activation in AIDS. Brain Pathol 11:306–312CrossRefPubMedGoogle Scholar
  31. Lehmann SM et al (2012) An unconventional role for miRNA: let-7 activates toll-like receptor 7 and causes neurodegeneration. Nat Neurosci 15:827–835CrossRefPubMedGoogle Scholar
  32. Lenassi M, Cagney G, Liao M, Vaupotic T, Bartholomeeusen K, Cheng Y, Krogan NJ, Plemenitas A, Peterlin BM (2010) HIV Nef is secreted in exosomes and triggers apoptosis in bystander CD4+ T cells. Traffic 11:110–122CrossRefPubMedPubMedCentralGoogle Scholar
  33. Li DM, Sun H (1997) TEP1, encoded by a candidate tumor suppressor locus, is a novel protein tyrosine phosphatase regulated by transforming growth factor beta. Cancer Res 57:2124–2129PubMedGoogle Scholar
  34. Maschke M, Kastrup O, Esser S, Ross B, Hengge U, Hufnagel A (2000) Incidence and prevalence of neurological disorders associated with HIV since the introduction of highly active antiretroviral therapy (HAART). J Neurol Neurosurg Psychiatry 69:376–380CrossRefPubMedPubMedCentralGoogle Scholar
  35. McArthur JC, Haughey N, Gartner S, Conant K, Pardo C, Nath A, Sacktor N (2003) Human immunodeficiency virus-associated dementia: an evolving disease. J Neuro-Oncol 9:205–221Google Scholar
  36. McArthur JC, Steiner J, Sacktor N, Nath A (2010) Human immunodeficiency virus-associated neurocognitive disorders: mind the gap. Ann Neurol 67:699–714PubMedGoogle Scholar
  37. Miyata S, Fukuda Y, Tojima H, Matsuzaki K, Kitanaka S, Sawada H (2015) Mechanism of the inhibition of leukemia cell growth and induction of apoptosis through the activation of ATR and PTEN by the topoisomerase inhibitor 3EZ, 20Ac-ingenol. Leuk Res 39:927–932CrossRefPubMedGoogle Scholar
  38. Narayanan A, Iordanskiy S, Das R, Van Duyne R, Santos S, Jaworski E, Guendel I, Sampey G, Dalby E, Iglesias-Ussel M, Popratiloff A, Hakami R, Kehn-Hall K, Young M, Subra C, Gilbert C, Bailey C, Romerio F, Kashanchi F (2013) Exosomes derived from HIV-1-infected cells contain trans-activation response element RNA. J Biol Chem 288:20014–20033CrossRefPubMedPubMedCentralGoogle Scholar
  39. Ning K, Pei L, Liao M, Liu B, Zhang Y, Jiang W, Mielke JG, Li L, Chen Y, El-Hayek YH, Fehlings MG, Zhang X, Liu F, Eubanks J, Wan Q (2004) Dual neuroprotective signaling mediated by downregulating two distinct phosphatase activities of PTEN. J Neurosci 24:4052–4060CrossRefPubMedGoogle Scholar
  40. Ojha CR, Lapierre J, Rodriguez M, Dever SM, Zadeh MA, DeMarino C, Pleet ML, Kashanchi F, El-Hage N (2017) Interplay between autophagy, exosomes and HIV-1 associated neurological disorders: new insights for diagnosis and therapeutic applications. Viruses 9Google Scholar
  41. Pegtel DM, Peferoen L, Amor S (2014) Extracellular vesicles as modulators of cell-to-cell communication in the healthy and diseased brain. Philos Trans R Soc Lond Ser B Biol Sci 369Google Scholar
  42. Periyasamy P, Guo ML, Buch S (2016) Cocaine induces astrocytosis through ER stress-mediated activation of autophagy. Autophagy 12:1310–1329CrossRefPubMedPubMedCentralGoogle Scholar
  43. Prinz M, Erny D, Hagemeyer N (2017) Ontogeny and homeostasis of CNS myeloid cells. Nat Immunol 18:385–392CrossRefPubMedGoogle Scholar
  44. Radhakrishnan B, Alwin Prem Anand A (2016) Role of miRNA-9 in brain development. J Exp Neurosci 10:101–120CrossRefPubMedPubMedCentralGoogle Scholar
  45. Rahimian P, He JJ (2016) Exosome-associated release, uptake, and neurotoxicity of HIV-1 tat protein. J Neuro-Oncol 22:774–788Google Scholar
  46. Raymond AD, Diaz P, Chevelon S, Agudelo M, Yndart-Arias A, Ding H, Kaushik A, Jayant RD, Nikkhah-Moshaie R, Roy U, Pilakka-Kanthikeel S, Nair MP (2016) Microglia-derived HIV Nef+ exosome impairment of the blood-brain barrier is treatable by nanomedicine-based delivery of Nef peptides. J Neuro-Oncol 22:129–139Google Scholar
  47. Rivest S (2009) Regulation of innate immune responses in the brain. Nat Rev Immunol 9:429–439CrossRefPubMedGoogle Scholar
  48. Rom S, Rom I, Passiatore G, Pacifici M, Radhakrishnan S, Del Valle L, Pina-Oviedo S, Khalili K, Eletto D, Peruzzi F (2010) CCL8/MCP-2 is a target for mir-146a in HIV-1-infected human microglial cells. FASEB J 24:2292–2300CrossRefPubMedPubMedCentralGoogle Scholar
  49. Sacktor N, McDermott MP, Marder K, Schifitto G, Selnes OA, McArthur JC, Stern Y, Albert S, Palumbo D, Kieburtz K, De Marcaida JA, Cohen B, Epstein L (2002) HIV-associated cognitive impairment before and after the advent of combination therapy. J Neuro-Oncol 8:136–142Google Scholar
  50. Sampey GC, Saifuddin M, Schwab A, Barclay R, Punya S, Chung MC, Hakami RM, Zadeh MA, Lepene B, Klase ZA, El-Hage N, Young M, Iordanskiy S, Kashanchi F (2016) Exosomes from HIV-1-infected cells stimulate production of pro-inflammatory cytokines through trans-activating response (TAR) RNA. J Biol Chem 291:1251–1266CrossRefPubMedGoogle Scholar
  51. Sanchez-Del Cojo M, Lopez-Huertas MR, Diez-Fuertes F, Rodriguez-Mora S, Bermejo M, Lopez-Campos G, Mateos E, Jimenez-Tormo L, Gomez-Esquer F, Diaz-Gil G, Alcami J, Coiras M (2017) Changes in the cellular microRNA profile by the intracellular expression of HIV-1 tat regulator: a potential mechanism for resistance to apoptosis and impaired proliferation in HIV-1 infected CD4+ T cells. PLoS One 12:e0185677CrossRefPubMedPubMedCentralGoogle Scholar
  52. Sempere LF, Keto J, Fabbri M (2017) Exosomal MicroRNAs in breast cancer towards diagnostic and therapeutic applications. Cancers (Basel) 9(71).  https://doi.org/10.3390/cancers9070071
  53. Shah A, Silverstein PS, Singh DP, Kumar A (2012) Involvement of metabotropic glutamate receptor 5, AKT/PI3K signaling and NF-kappaB pathway in methamphetamine-mediated increase in IL-6 and IL-8 expression in astrocytes. J Neuroinflammation 9:52CrossRefPubMedPubMedCentralGoogle Scholar
  54. Shelton MN, Huang MB, Ali SA, Powell MD, Bond VC (2012) Secretion modification region-derived peptide disrupts HIV-1 Nef's interaction with mortalin and blocks virus and Nef exosome release. J Virol 86:406–419CrossRefPubMedPubMedCentralGoogle Scholar
  55. Sun B, Dalvi P, Abadjian L, Tang N, Pulliam L (2017) Blood neuron-derived exosomes as biomarkers of cognitive impairment in HIV. AIDS 31(14):F9–F17CrossRefPubMedGoogle Scholar
  56. Tamura M, Gu J, Danen EH, Takino T, Miyamoto S, Yamada KM (1999) PTEN interactions with focal adhesion kinase and suppression of the extracellular matrix-dependent phosphatidylinositol 3-kinase/Akt cell survival pathway. J Biol Chem 274:20693–20703CrossRefPubMedGoogle Scholar
  57. Tarassishin L, Suh HS, Lee SC (2014) LPS and IL-1 differentially activate mouse and human astrocytes: role of CD14. Glia 62:999–1013CrossRefPubMedPubMedCentralGoogle Scholar
  58. Tosar JP, Cayota A, Eitan E, Halushka MK, Witwer KW (2017) Ribonucleic artefacts: are some extracellular RNA discoveries driven by cell culture medium components? J Extracell Vesicles 6:1272832CrossRefPubMedPubMedCentralGoogle Scholar
  59. Wang G, Shi Y, Jiang X, Leak RK, Hu X, Wu Y, Pu H, Li WW, Tang B, Wang Y, Gao Y, Zheng P, Bennett MV, Chen J (2015) HDAC inhibition prevents white matter injury by modulating microglia/macrophage polarization through the GSK3beta/PTEN/Akt axis. Proc Natl Acad Sci U S A 112:2853–2858CrossRefPubMedPubMedCentralGoogle Scholar
  60. Woodward NC, Levine MC, Haghani A, Shirmohammadi F, Saffari A, Sioutas C, Morgan TE, Finch CE (2017) Toll-like receptor 4 in glial inflammatory responses to air pollution in vitro and in vivo. J Neuroinflammation 14:84CrossRefPubMedPubMedCentralGoogle Scholar
  61. Xue M, Yao S, Hu M, Li W, Hao T, Zhou F, Zhu X, Lu H, Qin D, Yan Q, Zhu J, Gao SJ, Lu C (2014) HIV-1 Nef and KSHV oncogene K1 synergistically promote angiogenesis by inducing cellular miR-718 to regulate the PTEN/AKT/mTOR signaling pathway. Nucleic Acids Res 42:9862–9879CrossRefPubMedPubMedCentralGoogle Scholar
  62. Yang N, Chen J, Zhang H, Wang X, Yao H, Peng Y, Zhang W (2017) LncRNA OIP5-AS1 loss-induced microRNA-410 accumulation regulates cell proliferation and apoptosis by targeting KLF10 via activating PTEN/PI3K/AKT pathway in multiple myeloma. Cell Death Dis 8:e2975CrossRefPubMedPubMedCentralGoogle Scholar
  63. Yao H, Ma R, Yang L, Hu G, Chen X, Duan M, Kook Y, Niu F, Liao K, Fu M, Hu G, Kolattukudy P, Buch S (2014) MiR-9 promotes microglial activation by targeting MCPIP1. Nat Commun 5:4386CrossRefPubMedPubMedCentralGoogle Scholar
  64. Yelamanchili SV, Chaudhuri AD, Chen LN, Xiong H, Fox HS (2010) MicroRNA-21 dysregulates the expression of MEF2C in neurons in monkey and human SIV/HIV neurological disease. Cell Death Dis 1:e77CrossRefPubMedPubMedCentralGoogle Scholar
  65. Yelamanchili SV, Lamberty BG, Rennard DA, Morsey BM, Hochfelder CG, Meays BM, Levy E, Fox HS (2015) MiR-21 in extracellular vesicles leads to neurotoxicity via TLR7 signaling in SIV neurological disease. PLoS Pathog 11:e1005032CrossRefPubMedPubMedCentralGoogle Scholar
  66. Yu C, Narasipura SD, Richards MH, Hu XT, Yamamoto B, Al-Harthi L (2017) HIV and drug abuse mediate astrocyte senescence in a beta-catenin-dependent manner leading to neuronal toxicity. Aging Cell 16:956–965CrossRefPubMedPubMedCentralGoogle Scholar
  67. Zhang Y, Zhu T, Zhang X, Chao J, Hu G, Yao H (2015a) Role of high-mobility group box 1 in methamphetamine-induced activation and migration of astrocytes. J Neuroinflammation 12:156CrossRefPubMedPubMedCentralGoogle Scholar
  68. Zhang Y, Lv X, Bai Y, Zhu X, Wu X, Chao J, Duan M, Buch S, Chen L, Yao H (2015b) Involvement of sigma-1 receptor in astrocyte activation induced by methamphetamine via up-regulation of its own expression. J Neuroinflammation 12:29CrossRefPubMedPubMedCentralGoogle Scholar
  69. Zhao T, Adams MH, Zou SP, El-Hage N, Hauser KF, Knapp PE (2007) Silencing the PTEN gene is protective against neuronal death induced by human immunodeficiency virus type 1 tat. J Neuro-Oncol 13:97–106Google Scholar
  70. Zhou K, Zhong Q, Wang YC, Xiong XY, Meng ZY, Zhao T, Zhu WY, Liao MF, Wu LR, Yang YR, Liu J, Duan CM, Li J, Gong QW, Liu L, Yang MH, Xiong A, Wang J, Yang QW (2017) Regulatory T cells ameliorate intracerebral hemorrhage-induced inflammatory injury by modulating microglia/macrophage polarization through the IL-10/GSK3beta/PTEN axis. J Cereb Blood Flow Metab 37:967–979CrossRefPubMedGoogle Scholar
  71. Zou S, El-Hage N, Podhaizer EM, Knapp PE, Hauser KF (2011) PTEN gene silencing prevents HIV-1 gp120(IIIB)-induced degeneration of striatal neurons. J Neuro-Oncol 17:41–49Google Scholar

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

Personalised recommendations