Abstract
HIV-1 gp120 plays a critical role in the pathogenesis of HIV-associated pain, but the underlying molecular mechanisms are incompletely understood. This study aims to determine the effect and possible mechanism of HIV-1 gp120 on BDNF expression in BV2 cells (a murine-derived microglial cell line). We observed that gp120 (10 ng/ml) activated BV2 cells in cultures and upregulated proBDNF/mBDNF. Furthermore, gp120-treated BV2 also accumulated Wnt3a and β-catenin, suggesting the activation of the Wnt/β-catenin pathway. We demonstrated that activation of the pathway by Wnt3a upregulated BDNF expression. In contrast, inhibition of the Wnt/β-catenin pathway by either DKK1 or IWR-1 attenuated BDNF upregulation induced by gp120 or Wnt3a. These findings collectively suggest that gp120 stimulates BDNF expression in BV2 cells via the Wnt/β-catenin signaling pathway.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Abassi M et al (2016) Cerebrospinal fluid biomarkers and HIV-associated neurocognitive disorders in HIV-infected individuals in Rakai, Uganda. J Neurovirol. doi:10.1007/s13365-016-0505-9
Al-Harthi L (2012) Interplay between Wnt/beta-catenin signaling and HIV: virologic and biologic consequences in the CNS. J Neuroimmune Pharmacol 7:731–739. doi:10.1007/s11481-012-9411-y
Bachis A, Aden SA, Nosheny RL, Andrews PM, Mocchetti I (2006) Axonal transport of human immunodeficiency virus type 1 envelope protein glycoprotein 120 is found in association with neuronal apoptosis. The Journal of neuroscience: the official journal of the Society for Neuroscience 26:6771–6780. doi:10.1523/JNEUROSCI.1054-06.2006
Bachis A, Biggio F, Major EO, Mocchetti I (2009) M- and T-tropic HIVs promote apoptosis in rat neurons. J Neuroimmune Pharmacol 4:150–160. doi:10.1007/s11481-008-9141-3
Bachis A, Cruz MI, Mocchetti I (2010) M-tropic HIV envelope protein gp120 exhibits a different neuropathological profile than T-tropic gp120 in rat striatum. Eur J Neurosci 32:570–578. doi:10.1111/j.1460-9568.2010.07325.x
Bashir T, Patgaonkar M, Kumar SC, Pasi A, Reddy KV (2015) HbAHP-25, an in-silico designed peptide, inhibits HIV-1 entry by blocking gp120 binding to CD4 receptor. PLoS One 10:e0124839. doi:10.1371/journal.pone.0124839
Beggs S, Salter MW (2013) The known knowns of microglia-neuronal signalling in neuropathic pain. Neurosci Lett 557 Pt A:37–42. doi:10.1016/j.neulet.2013.08.037
Bissel SJ, Wiley CA (2004) Human immunodeficiency virus infection of the brain: pitfalls in evaluating infected/affected cell populations. Brain Pathol 14:97–108
Blasi E, Barluzzi R, Bocchini V, Mazzolla R, Bistoni F (1990) Immortalization of murine microglial cells by a v-raf/v-myc carrying retrovirus. J Neuroimmunol 27:229–237
Borrell-Pages M et al (2006) Cystamine and cysteamine increase brain levels of BDNF in Huntington disease via HSJ1b and transglutaminase. J Clin Invest 116:1410–1424. doi:10.1172/JCI27607
Butler JS, Dunning EC, Murray DW, Doran PP, O'Byrne JM (2013) HIV-1 protein induced modulation of primary human osteoblast differentiation and function via a Wnt/beta-catenin-dependent mechanism. Journal of orthopaedic research: official publication of the Orthopaedic Research Society 31:218–226. doi:10.1002/jor.22196
Cai Q, Li Y, Mao J, Pei G (2016) Neurogenesis-promoting natural product alpha-Asarone modulates morphological dynamics of activated microglia. Front Cell Neurosci 10:280. doi:10.3389/fncel.2016.00280
Carrillo J et al (2015) Gp120/CD4 blocking antibodies are frequently elicited in ART-naive chronically HIV-1 infected individuals. PLoS One 10:e0120648. doi:10.1371/journal.pone.0120648
Chen B et al (2009) Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. Nat Chem Biol 5:100–107. doi:10.1038/nchembio.137
Chen BY, Wang X, Wang ZY, Wang YZ, Chen LW, Luo ZJ (2013) Brain-derived neurotrophic factor stimulates proliferation and differentiation of neural stem cells, possibly by triggering the Wnt/beta-catenin signaling pathway. J Neurosci Res 91:30–41. doi:10.1002/jnr.23138
Coull JA et al (2005) BDNF from microglia causes the shift in neuronal anion gradient underlying neuropathic pain. Nature 438:1017–1021. doi:10.1038/nature04223
Crotti A et al (2014) Mutant Huntingtin promotes autonomous microglia activation via myeloid lineage-determining factors. Nat Neurosci 17:513–521. doi:10.1038/nn.3668
Das A et al (2016) Transcriptome sequencing reveals that LPS-triggered transcriptional responses in established microglia BV2 cell lines are poorly representative of primary microglia. J Neuroinflammation 13:182. doi:10.1186/s12974-016-0644-1
Harte-Hargrove LC, Maclusky NJ, Scharfman HE (2013) Brain-derived neurotrophic factor-estrogen interactions in the hippocampal mossy fiber pathway: implications for normal brain function and disease. Neuroscience 239:46–66. doi:10.1016/j.neuroscience.2012.12.029
He J et al (1997) CCR3 and CCR5 are co-receptors for HIV-1 infection of microglia. Nature 385:645–649. doi:10.1038/385645a0
Henn A, Lund S, Hedtjarn M, Schrattenholz A, Porzgen P, Leist M (2009) The suitability of BV2 cells as alternative model system for primary microglia cultures or for animal experiments examining brain inflammation. ALTEX 26:83–94
Inoue K (2007) Involvement of microglia in neuropathic pain signalling. Brain and nerve = Shinkei kenkyu no shinpo 59:739–746
Inoue K (2009) The mechanism and control of neuropathic pain. Rinsho shinkeigaku = Clinical neurology 49:779–782
Itokazu T, Hayano Y, Takahashi R, Yamashita T (2014) Involvement of Wnt/beta-catenin signaling in the development of neuropathic pain. Neurosci Res 79:34–40. doi:10.1016/j.neures.2013.12.002
Kim HY, Park EJ, Joe EH, Jou I (2003) Curcumin suppresses Janus kinase-STAT inflammatory signaling through activation of Src homology 2 domain-containing tyrosine phosphatase 2 in brain microglia. J Immunol 171:6072–6079
L'Episcopo F et al (2014) Targeting Wnt signaling at the neuroimmune interface for dopaminergic neuroprotection/repair in Parkinson's disease. J Mol Cell Biol 6:13–26. doi:10.1093/jmcb/mjt053
Li CQ, Xu JM, Liu D, Zhang JY, Dai RP (2008) Brain derived neurotrophic factor (BDNF) contributes to the pain hypersensitivity following surgical incision in the rats. Mol Pain 4:27. doi:10.1186/1744-8069-4-27
Li B, Shi Y, Shu J, Gao J, Wu P, Tang SJ (2013) Wingless-type mammary tumor virus integration site family, member 5A (Wnt5a) regulates human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein 120 (gp120)-induced expression of pro-inflammatory cytokines via the Ca2+/calmodulin-dependent protein kinase II (CaMKII) and c-Jun N-terminal kinase (JNK) signaling pathways. J Biol Chem 288:13610–13619. doi:10.1074/jbc.M112.381046
Lu J et al (2009) Structure-activity relationship studies of small-molecule inhibitors of Wnt response. Bioorg Med Chem Lett 19:3825–3827. doi:10.1016/j.bmcl.2009.04.040
Manosso LM, Moretti M, Ribeiro CM, Goncalves FM, Leal RB, Rodrigues AL (2015) Antidepressant-like effect of zinc is dependent on signaling pathways implicated in BDNF modulation. Prog Neuro-Psychopharmacol Biol Psychiatry 59:59–67. doi:10.1016/j.pnpbp.2015.01.008
Masliah E, Ge N, Mucke L (1996) Pathogenesis of HIV-1 associated neurodegeneration. Crit Rev Neurobiol 10:57–67
Merighi A, Salio C, Ghirri A, Lossi L, Ferrini F, Betelli C, Bardoni R (2008) BDNF as a pain modulator. Prog Neurobiol 85:297–317. doi:10.1016/j.pneurobio.2008.04.004
Mitchelmore C, Gede L (2014) Brain derived neurotrophic factor: epigenetic regulation in psychiatric disorders. Brain Res 1586:162–172. doi:10.1016/j.brainres.2014.06.037
Moore JP, Trkola A, Dragic T (1997) Co-receptors for HIV-1 entry. Curr Opin Immunol 9:551–562
Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63
Nath S, Bachani M, Harshavardhana D, Steiner JP (2012) Catechins protect neurons against mitochondrial toxins and HIV proteins via activation of the BDNF pathway. J Neurovirol 18:445–455. doi:10.1007/s13365-012-0122-1
Nosheny RL, Mocchetti I, Bachis A (2005) Brain-derived neurotrophic factor as a prototype neuroprotective factor against HIV-1-associated neuronal degeneration. Neurotox Res 8:187–198
Notaras M, Hill R, van den Buuse M (2015) A role for the BDNF gene Val66Met polymorphism in schizophrenia? A comprehensive review. Neurosci Biobehav Rev 51:15–30. doi:10.1016/j.neubiorev.2014.12.016
Phillips HS, Hains JM, Armanini M, Laramee GR, Johnson SA, Winslow JW (1991) BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer's disease. Neuron 7:695–702
Pierson TC, Doms RW, Pohlmann S (2004) Prospects of HIV-1 entry inhibitors as novel therapeutics. Rev Med Virol 14:255–270. doi:10.1002/rmv.435
Reinhart V, Bove SE, Volfson D, Lewis DA, Kleiman RJ, Lanz TA (2015) Evaluation of TrkB and BDNF transcripts in prefrontal cortex, hippocampus, and striatum from subjects with schizophrenia, bipolar disorder, and major depressive disorder. Neurobiol Dis 77:220–227. doi:10.1016/j.nbd.2015.03.011
Roy A, Jana A, Yatish K, Freidt MB, Fung YK, Martinson JA, Pahan K (2008) Reactive oxygen species up-regulate CD11b in microglia via nitric oxide: implications for neurodegenerative diseases. Free Radic Biol Med 45:686–699. doi:10.1016/j.freeradbiomed.2008.05.026
Ru W, Tang SJ (2016) HIV-1 gp120Bal down-regulates phosphorylated NMDA receptor subunit 1 in cortical neurons via activation of glutamate and chemokine receptors. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 11:182–191. doi:10.1007/s11481-015-9644-7
Shi Y, Shu J, Gelman BB, Lisinicchia JG, Tang SJ (2013) Wnt signaling in the pathogenesis of human HIV-associated pain syndromes. Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 8:956–964. doi:10.1007/s11481-013-9474-4
Soontornniyomkij V, Wang G, Pittman CA, Wiley CA, Achim CL (1998) Expression of brain-derived neurotrophic factor protein in activated microglia of human immunodeficiency virus type 1 encephalitis. Neuropathol Appl Neurobiol 24:453–460
Stuke H, Hellweg R, Bermpohl F (2012) The development of depression: the role of brain-derived neurotrophic factor. Nervenarzt 83:869–877. doi:10.1007/s00115-011-3374-8
Tapia-Arancibia L, Aliaga E, Silhol M, Arancibia S (2008) New insights into brain BDNF function in normal aging and Alzheimer disease. Brain Res Rev 59:201–220. doi:10.1016/j.brainresrev.2008.07.007
Taves S, Berta T, Chen G, Ji RR (2013) Microglia and spinal cord synaptic plasticity in persistent pain. Neural plasticity 2013:753656. doi:10.1155/2013/753656
Taylor AM et al (2015) Microglia disrupt mesolimbic reward circuitry in chronic pain. The Journal of neuroscience: the official journal of the Society for Neuroscience 35:8442–8450. doi:10.1523/JNEUROSCI.4036-14.2015
Venkatachari NJ et al (2016) Transcriptome analyses identify key cellular factors associated with HIV-1 associated neuropathogenesis in infected men. AIDS. doi:10.1097/QAD.0000000000001379
Yuan SB et al (2014) Gp120 in the pathogenesis of human immunodeficiency virus-associated pain. Ann Neurol 75:837–850. doi:10.1002/ana.24139
Zhang XY, Chen DC, Tan YL, Tan SP, Luo X, Zuo L, Soares JC (2016) BDNF polymorphisms are associated with schizophrenia onset and positive symptoms. Schizophr Res 170:41–47. doi:10.1016/j.schres.2015.11.009
Zhu ZW, Friess H, Wang L, Zimmermann A, Buchler MW (2001) Brain-derived neurotrophic factor (BDNF) is upregulated and associated with pain in chronic pancreatitis. Dig Dis Sci 46:1633–1639
Acknowledgements
WPZ was financially supported by the Public Technology Application Research Project from Science Technology Bureau of Zhejiang Province (2016C33080), China. SJT was supported by NIH grants: R01NS095747, R01NS079166 and R01DA036165.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of Interest
The authors declare that they have no conflict of interest.
Rights and permissions
About this article
Cite this article
Wang, Y., Liao, J., Tang, SJ. et al. HIV-1 gp120 Upregulates Brain-Derived Neurotrophic Factor (BDNF) Expression in BV2 Cells via the Wnt/β-Catenin Signaling Pathway. J Mol Neurosci 62, 199–208 (2017). https://doi.org/10.1007/s12031-017-0931-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12031-017-0931-z