Skip to main content

Advertisement

SpringerLink
Log in

Human endogenous retrovirus W env increases nitric oxide production and enhances the migration ability of microglia by regulating the expression of inducible nitric oxide synthase

  • Research Article
  • Published:
Virologica Sinica

Abstract

Human endogenous retrovirus W env (HERV-W env) plays a critical role in many neuropsychological diseases such as schizophrenia and multiple sclerosis (MS). These diseases are accompanied by immunological reactions in the central nervous system (CNS). Microglia are important immunocytes in brain inflammation that can produce a gasotransmitter–nitric oxide (NO). NO not only plays a role in the function of neuronal cells but also participates in the pathogenesis of various neuropsychological diseases. In this study, we reported increased NO production in CHME-5 microglia cells after they were transfected with HERV-W env. Moreover, HERV-W env increased the expression and function of human inducible nitric oxide synthase (hiNOS) and enhanced the promoter activity of hiNOS. Microglial migration was also enhanced. These data revealed that HERV-W env might contribute to increase NO production and microglial migration ability in neuropsychological disorders by regulating the expression of inducible NOS. Results from this study might lead to the identification of novel targets for the treatment of neuropsychological diseases, including neuroinflammatory diseases, stroke, and neurodegenerative diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Adachi R, Matsui S, Kinoshita M, Nagaishi K, Sasaki H, Kasahara T, Suzuki K. 2000. Nitric oxide induces chemotaxis of neutrophil- like HL-60 cells and translocation of cofilin to plasma membranes. Int J Immunopharmacol, 22: 855–864.

    Article  CAS  PubMed  Google Scholar 

  • Alderton WK, Cooper CE, Knowles RG. 2001. Nitric oxide synthases: structure, function and inhibition. Biochem J, 357: 593–615.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Antony JM, Ellestad KK, Hammond R, Imaizumi K, Mallet F, Warren KG, Power C. 2007. The human endogenous retrovirus envelope glycoprotein, syncytin-1, regulates neuroinflamma-tion and its receptor expression in multiple sclerosis: a role for endoplasmic reticulum chaperones in astrocytes. J Immunol, 179: 1210–1224.

    Article  CAS  PubMed  Google Scholar 

  • Antony JM, van Marle G, Opii W, Butterfield DA, Mallet F, Yong VW, Wallace JL, Deacon RM, Warren K, Power C. 2004. Human endogenous retrovirus glycoprotein-mediated induction of redox reactants causes oligodendrocyte death and demyelination. Nat Neurosci, 7: 1088–1095.

    Article  CAS  PubMed  Google Scholar 

  • Asiimwe N, Yeo SG, Kim MS, Jung J, Jeong NY. 2016. Nitric Oxide: Exploring the Contextual Link with Alzheimer’s Disease. Oxid Med Cell Longev, 2016: 7205747.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Bao J, Zhu J, Luo S, Cheng Y, Zhou S. 2016. CXCR7 suppression modulates microglial chemotaxis to ameliorate experimentally-induced autoimmune encephalomyelitis. Biochem Biophy Res Commun, 469: 1–7.

    Article  CAS  Google Scholar 

  • Bjerregaard B, Holck S, Christensen IJ, Larsson LI. 2006. Syncytin is involved in breast cancer-endothelial cell fusions. Cell Mol Life Sci, 63: 1906–1911.

    Article  CAS  PubMed  Google Scholar 

  • Brodsky I, Foley B, Gillespie D. 1993. Expression of human endogenous retrovirus (HERV-K) in chronic myeloid leukemia. Leuk Lymphoma, 11 Suppl 1: 119–123.

    Article  Google Scholar 

  • Clausen J. 2003. Endogenous retroviruses and MS: using ERVs as disease markers. Int MS J, 10: 22–28.

    CAS  PubMed  Google Scholar 

  • Colton CA. 2009. Heterogeneity of microglial activation in the innate immune response in the brain. J Neuroimmune Pharmacol, 4: 399–418.

    Article  PubMed  PubMed Central  Google Scholar 

  • Conrad B, Weissmahr RN, Boni J, Arcari R, Schupbach J, Mach B. 1997. A human endogenous retroviral superantigen as candidate autoimmune gene in type I diabetes. Cell, 90: 303–313.

    Article  CAS  PubMed  Google Scholar 

  • Czeh M, Gressens P, Kaindl AM. 2011. The yin and yang of microglia. Dev Neurosci, 33: 199–209.

    Article  CAS  PubMed  Google Scholar 

  • de Vera ME, Shapiro RA, Nussler AK, Mudgett JS, Simmons RL, Morris SJ, Billiar TR, Geller DA. 1996. Transcriptional regulation of human inducible nitric oxide synthase (NOS2) gene by cytokines: initial analysis of the human NOS2 promoter. Proc Natl Acad Sci U S A, 93: 1054–1059.

    Article  PubMed  PubMed Central  Google Scholar 

  • Draheim HJ, Prinz M, Weber JR, Weiser T, Kettenmann H, Hanisch UK. 1999. Induction of potassium channels in mouse brain microglia: cells acquire responsiveness to pneumococcal cell wall components during late development. Neuroscience, 89: 1379–1390.

    Article  CAS  PubMed  Google Scholar 

  • Dzoljic E, Grbatinic I, Kostic V. 2015. Why is nitric oxide important for our brain?. Funct Neurol, 30: 159–163.

    PubMed  PubMed Central  Google Scholar 

  • Frendo JL, Olivier D, Cheynet V, Blond JL, Bouton O, Vidaud M, Rabreau M, Evain-Brion D, Mallet F. 2003. Direct involvement of HERV-W Env glycoprotein in human trophoblast cell fusion and differentiation. Mol Cell Biol, 23: 3566–3574.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fuseler JW, Valarmathi MT. 2016. Nitric Oxide Modulates Postnatal Bone Marrow-Derived Mesenchymal Stem Cell Migration. Front Cell Dev Biol, 4: 133.

    Article  PubMed  PubMed Central  Google Scholar 

  • Galea E, Feinstein DL, Reis DJ. 1992. Induction of calcium-independent nitric oxide synthase activity in primary rat glial cultures. Proc Natl Acad Sci U S A, 89: 10945–10949.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ghasemi M, Fatemi A. 2014. Pathologic role of glial nitric oxide in adult and pediatric neuroinflammatory diseases. Neuroscience & Biobehavioral Reviews, 45: 168–182.

    Article  CAS  Google Scholar 

  • Gimenez J, Montgiraud C, Pichon JP, Bonnaud B, Arsac M, Ruel K, Bouton O, Mallet F. 2010. Custom human endogenous retroviruses dedicated microarray identifies self-induced HERV-W family elements reactivated in testicular cancer upon methylation control. Nucleic Acids Res, 38: 2229–2246.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hanisch UK, Kettenmann H. 2007. Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci, 10: 1387–1394.

    Article  CAS  PubMed  Google Scholar 

  • Huang W, Li S, Hu Y, Yu H, Luo F, Zhang Q, Zhu F. 2011. Implication of the env gene of the human endogenous retrovirus W family in the expression of BDNF and DRD3 and development of recent-onset schizophrenia. Schizophr Bull, 37: 988–1000.

    Article  PubMed  Google Scholar 

  • Huang W, Liu Z, Wei W, Wang G, Wu J, Zhu F. 2006. Human endogenous retroviral pol RNA and protein detected and identified in the blood of individuals with schizophrenia. Schizophr Res, 83: 193–199.

    Article  PubMed  Google Scholar 

  • Jaffrey SR, Snyder SH. 1995. Nitric oxide: a neural messenger. Annu Rev Cell Dev Biol, 11: 417–440.

    Article  CAS  PubMed  Google Scholar 

  • Janabi N, Peudenier S, Heron B, Ng KH, Tardieu M. 1995. Establishment of human microglial cell lines after transfection of primary cultures of embryonic microglial cells with the SV40 large T antigen. Neurosci Lett, 195: 105–108.

    Article  CAS  PubMed  Google Scholar 

  • Jern P, Sperber GO, Blomberg J. 2004. Definition and variation of human endogenous retrovirus H. Virology, 327: 93–110.

    Article  CAS  PubMed  Google Scholar 

  • Karlsson H, Schroder J, Bachmann S, Bottmer C, Yolken RH. 2004. HERV-W-related RNA detected in plasma from individuals with recent-onset schizophrenia or schizoaffective disorder. Mol Psychiatry, 9: 12–13.

    Article  CAS  PubMed  Google Scholar 

  • Klegeris A, McGeer EG, McGeer PL. 2007. Therapeutic approaches to inflammation in neurodegenerative disease. Curr Opin Neurol, 20: 351–357.

    Article  CAS  PubMed  Google Scholar 

  • Ko HM, Kim SY, Joo SH, Yang SI, Shin CY, Koo BN. 2013. Synergistic activation of lipopolsaccharide-stimulated glial cells by propofol. Biochem Biophys Res Commun, 438: 420–426.

    Article  CAS  PubMed  Google Scholar 

  • Kumar S, Singh RK, Bhardwaj TR. 2017. Therapeutic role of nitric oxide as emerging molecule. Biomed Pharmacother, 85: 182–201.

    Article  CAS  PubMed  Google Scholar 

  • Lefer AM, Lefer DJ. 1999. Nitric oxide. II. Nitric oxide protects in intestinal inflammation. Am J Physiol, 276: G572–G575.

    CAS  PubMed  Google Scholar 

  • Li S, Liu ZC, Yin SJ, Chen YT, Yu HL, Zeng J, Zhang Q, Zhu F. 2013. Human endogenous retrovirus W family envelope gene activates the small conductance Ca2+-activated K+ channel in human neuroblastoma cells through CREB. Neuroscience, 247: 164–174.

    Article  CAS  PubMed  Google Scholar 

  • Li H, Liu B, Huang J, Chen H, Guo X, Yuan Z. 2013. Insulin inhibits lipopolysaccharide-induced nitric oxide synthase expression in rat primary astrocytes. Brain Res, 1506: 1–11.

    Article  CAS  PubMed  Google Scholar 

  • Li W, Yang F, Liu Y, Gong R, Liu L, Feng Y, Hu P, Sun W, Hao Q, Kang L, Wu J, Zhu Y. 2009. Negative feedback regulation of IL-32 production by iNOS activation in response to dsRNA or influenza virus infection.

  • Eur J Immunol, 39: 1019–1024.

  • Lu A, Wang L, Qian L. 2015. The role of eNOS in the migration and proliferation of bone-marrow derived endothelial progenitor cells and in vitro angiogenesis. Cell Biol Int, 39: 484–490.

    Article  CAS  PubMed  Google Scholar 

  • Maeda T, Inagaki M, Fujita Y, Kimoto T, Tanabe-Fujimura C, Zou K, Liu J, Liu S, Komano H. 2016. ATP increases the migration of microglia across the brain endothelial cell monolayer. Biosci Rep, 36: e00318.

    Article  CAS  Google Scholar 

  • Mallet F, Bouton O, Prudhomme S, Cheynet V, Oriol G, Bonnaud B, Lucotte G, Duret L, Mandrand B. 2004. The endogenous retroviral locus ERVWE1 is a bona fide gene involved in hominoid placental physiology. Proc Natl Acad Sci U S A, 101: 1731–1736.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mameli G, Astone V, Arru G, Marconi S, Lovato L, Serra C, Sotgiu S, Bonetti B, Dolei A. 2007. Brains and peripheral blood mononuclear cells of multiple sclerosis (MS) patients hyperexpress MS-associated retrovirus/HERV-W endogenous retrovirus, but not Human herpesvirus 6. J Gen Virol, 88: 264–274.

    Article  CAS  PubMed  Google Scholar 

  • Mi S, Lee X, Li X, Veldman GM, Finnerty H, Racie L, LaVallie E, Tang XY, Edouard P, Howes S, Keith JJ, McCoy JM. 2000. Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature, 403: 785–789.

    Article  CAS  PubMed  Google Scholar 

  • Moussaud S, Lamodiere E, Savage C, Draheim HJ. 2009. Characterisation of K+ currents in the C8-B4 microglial cell line and their regulation by microglia activating stimuli. Cell Physiol Biochem, 24: 141–152.

    Article  CAS  PubMed  Google Scholar 

  • Mustafa AK, Gadalla MM, Snyder SH. 2009. Signaling by gasotransmitters. Sci Signal, 2: e2.

    Google Scholar 

  • Nakagawa K, Brusic V, McColl G, Harrison LC. 1997. Direct evidence for the expression of multiple endogenous retroviruses in the synovial compartment in rheumatoid arthritis. Arthritis Rheum, 40: 627–638.

    Article  CAS  PubMed  Google Scholar 

  • Nakamura T, Cho DH, Lipton SA. 2012. Redox regulation of protein misfolding, mitochondrial dysfunction, synaptic damage, and cell death in neurodegenerative diseases. Exp Neurol, 238: 12–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Perron H, Garson JA, Bedin F, Beseme F, Paranhos-Baccala G, Komurian-Pradel F, Mallet F, Tuke PW, Voisset C, Blond JL, Lalande B, Seigneurin JM, Mandrand B. 1997. Molecular identification of a novel retrovirus repeatedly isolated from patients with multiple sclerosis. The Collaborative Research Group on Multiple Sclerosis. Proc Natl Acad Sci U S A, 94: 7583–7588.

    Article  CAS  Google Scholar 

  • Perron H, Germi R, Bernard C, Garcia-Montojo M, Deluen C, Farinelli L, Faucard R, Veas F, Stefas I, Fabriek BO, Van-Horssen J, Van-der-Valk P, Gerdil C, Mancuso R, Saresella M, Clerici M, Marcel S, Creange A, Cavaretta R, Caputo D, Arru G, Morand P, Lang AB, Sotgiu S, Ruprecht K, Rieckmann P, Villoslada P, Chofflon M, Boucraut J, Pelletier J, Hartung HP. 2012. Human endogenous retrovirus type W envelope expression in blood and brain cells provides new insights into multiple sclerosis disease. Mult Scler, 18: 1721–1736.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Perron H, Lazarini F, Ruprecht K, Pechoux-Longin C, Seilhean D, Sazdovitch V, Creange A, Battail-Poirot N, Sibai G, Santoro L, Jolivet M, Darlix JL, Rieckmann P, Arzberger T, Hauw JJ, Lassmann H. 2005. Human endogenous retrovirus (HERV)-W ENV and GAG proteins: physiological expression in human brain and pathophysiological modulation in multiple sclerosis lesions. J Neurovirol, 11: 23–33.

    Article  CAS  PubMed  Google Scholar 

  • Qin C, Li S, Yan Q, Wang X, Chen Y, Zhou P, Lu M, Zhu F. 2016. Elevation of Ser9 phosphorylation of GSK3ß is required for HERV-W env-mediated BDNF signaling in human U251 cells. Neurosci Lett, 627: 84–91.

    Article  CAS  PubMed  Google Scholar 

  • Saha RN, Pahan K. 2006. Regulation of inducible nitric oxide synthase gene in glial cells. Antioxid Redox Signal, 8: 929–947.

    Article  CAS  PubMed  Google Scholar 

  • Saha RN, Pahan K. 2006b. Signals for the induction of nitric oxide synthase in astrocytes. Neurochem Int, 49: 154–163.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sang J, Chen Y, Tao Y. 2011. Nitric oxide inhibits gastric cancer cell growth through the modulation of the Akt pathway. Mol Med Rep, 4: 1163–1167.

    CAS  PubMed  Google Scholar 

  • Scheiblich H, Roloff F, Singh V, Stangel M, Stern M, Bicker G. 2014. Nitric oxide/cyclic GMP signaling regulates motility of a microglial cell line and primary microglia in vitro. Brain Res, 1564: 9–21.

    Article  CAS  PubMed  Google Scholar 

  • Seifarth W, Baust C, Murr A, Skladny H, Krieg-Schneider F, Blusch J, Werner T, Hehlmann R, Leib-Mosch C. 1998. Proviral structure, chromosomal location, and expression of HERV-KT47D, a novel human endogenous retrovirus derived from T47D particles. J Virol, 72: 8384–8391.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shaikh SB, Uy B, Perera A, Nicholson LFB. 2012. AGEs-RAGE mediated up-regulation of connexin43 in activated human microglial CHME-5 cells. Neurochem Int, 60: 640–651.

    Article  CAS  PubMed  Google Scholar 

  • Wallace JL. 2005. Nitric oxide as a regulator of inflammatory processes. Mem Inst Oswaldo Cruz, 100 Suppl 1: 5–9.

    Article  Google Scholar 

  • Wang-Johanning F, Liu J, Rycaj K, Huang M, Tsai K, Rosen DG, Chen DT, Lu DW, Barnhart KF, Johanning GL. 2007. Expression of multiple human endogenous retrovirus surface envelope proteins in ovarian cancer. Int J Cancer, 120: 81–90.

    Article  CAS  PubMed  Google Scholar 

  • Yolken RH, Torrey EF. 1995. Viruses, schizophrenia, and bipolar disorder. Clin Microbiol Rev, 8: 131–145.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yu H, Liu T, Zhao Z, Chen Y, Zeng J, Liu S, Zhu F. 2014. Mutations in 3’-long terminal repeat of HERV-W family in chromosome 7 upregulate syncytin-1 expression in urothelial cell carcinoma of the bladder through interacting with c-Myb. Oncogene, 33: 3947–3958.

    Article  CAS  PubMed  Google Scholar 

  • Yun HY, Dawson VL, Dawson TM. 1997. Nitric oxide in health and disease of the nervous system. Mol Psychiatry, 2: 300–310.

    Article  CAS  PubMed  Google Scholar 

  • Zhang Z, Cao Z, Liu C, Li R, Wang W, Wang X. 2016. MiRNAEmbedded ShRNAs for Radiation-Inducible LGMN Knockdown and the Antitumor Effects on Breast Cancer. Plos One, 11: e163446.

    Google Scholar 

  • Zhou L, Zhang H, Wu J. 2016. Effects of nitric oxide on the biological behavior of HepG2 human hepatocellular carcinoma cells. Exp Ther Med, 11: 1875–1880.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhou Y, Zhao Y, Gao Y, Hu W, Qu Y, Lou N, Zhu Y, Zhang X, Yang H. 2017. Hepatitis C virus NS3 protein enhances hepatocellular carcinoma cell invasion by promoting PPM1A ubiquitination and degradation. J Exp Clin Cancer Res, 36: 42.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  • Zhu T, Yao Q, Wang W, Yao H, Chao J. 2016. iNOS Induces Vascular Endothelial Cell Migration and Apoptosis Via Autophagy in Ischemia/Reperfusion Injury. Cell Physiol Biochem, 38: 1575–1588.

    Article  CAS  PubMed  Google Scholar 

  • Zipp F, Aktas O. 2006. The brain as a target of inflammation: common pathways link inflammatory and neurodegenerative diseases. Trends Neurosci, 29: 518–527.

    Article  CAS  PubMed  Google Scholar 

  • Zou F, Liu Y, Liu L, Wu K, Wei W, Zhu Y, Wu J. 2007. Retinoic acid activates human inducible nitric oxide synthase gene through binding of RARa/RXRa heterodimer to a novel retinoic acid response element in the promoter. Biochem Biophys Res Commun, 355: 494–500.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the National Natural Sciences Foundation of China (No. 31470264, No. 81271820, No. 30870789, and No. 30300117), the Key Program of Natural Science Foundation of Hubei Province of China (No. 2014CFA078), the Stanley Foundation from the Stanley Medical Research Institute (SMRI), USA (No. 06R-1366), to Dr. Fan Zhu and the Scientific Innovation Team Project of Hubei Province of China (No. 2015CFA009).

Author information

Authors and Affiliations

  1. Department of Medical Microbiology, School of Medicine, Wuhan University, Wuhan, 430071, China

    Ran Xiao, Xiuling Wang, Qiujin Yan, Xiaoning Tu & Fan Zhu

  2. Department of Integrated Medicine, Dongfeng Hospital, Hubei University of Medicine, Wuhan, 442000, China

    Shan Li

  3. Department of Neurology Medicine, Renmin Hospital of Wuhan University, Wuhan, 430060, China

    Qian Cao

  4. The State Key Laboratory of Virology, College of Life Sciences, Wuhan University, Wuhan, 430072, China

    Ying Zhu

  5. Hubei Province Key Laboratory of Allergy and Immunology, Wuhan, 430071, China

    Fan Zhu

Authors
  1. Ran Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Qian Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiuling Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qiujin Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiaoning Tu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ying Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Fan Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Fan Zhu.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xiao, R., Li, S., Cao, Q. et al. Human endogenous retrovirus W env increases nitric oxide production and enhances the migration ability of microglia by regulating the expression of inducible nitric oxide synthase. Virol. Sin. 32, 216–225 (2017). https://doi.org/10.1007/s12250-017-3997-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12250-017-3997-4

Keywords

Search

Navigation