Journal of Neuroimmune Pharmacology

, Volume 12, Issue 1, pp 133–151 | Cite as

Galectin-1 Reduces Neuroinflammation via Modulation of Nitric Oxide-Arginase Signaling in HIV-1 Transfected Microglia: a Gold Nanoparticle-Galectin-1 “Nanoplex” a Possible Neurotherapeutic?

  • Ravikumar Aalinkeel
  • Courtney S. Mangum
  • Eliane Abou-Jaoude
  • Jessica L. Reynolds
  • Maixian Liu
  • Karin Sundquist
  • Neil U. Parikh
  • Lee D. Chaves
  • Manoj J. Mammen
  • Stanley A. Schwartz
  • Supriya D. MahajanEmail author


Galectins are a family of β-galactoside-binding lectins that are important modulators of homeostasis in the central nervous system (CNS). Galectin-1 is a pivotal regulator of microglia activation that alters the immune balance from neurodegeneration to neuroprotection and could have therapeutic relevance in HIV associated neurocognitive disorders (HAND). We have previously shown that galectin-1 treatment decreased oxidative stress in microglia and hypothesize that the mechanism underlying this phenomenon is the cross regulatory interactions between Nitric oxide (NO) and Arginase I activity in microglia. We induced microglial activation and examined the effect of galectin-1 on the expression of various M1/M2 microglial phenotypic markers. Since, TNF-α is associated with activation of microglial cells involved in pathogenesis of neurodegenerative diseases, we treated HIV transfected human microglial cell cultures (CHME-5/HIV) with TNF-α followed by treatment with galectin-1, to examine the galectin-1 mediated neuro-modulatory response. Our results show that treatment of CHME-5/HIV microglia with galectin-1 reduced TNF-α induced oxidative stress by ~40%, and also significantly reduced iNOS gene expression and NO production while correspondingly increasing arginase-1, cationic amino acid transporter (CAT-1) gene expression and arginase activity. Galectin-1 treatment results in shifting microglia polarization from M1 toward the beneficial M2 phenotype which may prevent neurodegeneration and promote neuroprotection. Thus, our data suggests that galectin-1 treatment reduces neuroinflammation in the CNS microenvironment via the modulation of the NO-arginase network in microglia and thus could play a neuroprotective role in HAND. Further, the therapeutic potential of galectin-1 could be enhanced by conjugation of galectin-1 onto gold nanoparticles (Au-NP), resulting in a nanogold-galectin-1 (Au-Gal-1) multivalent complex that will have more clinical translational efficacy than free galectin-1 by virtue of increasing the payload influx.


Arginase Microglia HIV-1 associated neurological disorders (HAND) M1/M2 phenotype Nitric oxide Galectin-1 



The authors who like to acknowledge the funding support from the Dr. Louis Sklarow Memorial Trust 2015-2016 (Mahajan SD) and the New York State Department of Health (DOH) funded Empire Clinical Research Investigator Program (ECRIP) (Schwartz SA). The authors are extremely grateful to Dr. Jonathan Karn, Chairman and Reinberger Professor of Molecular Biology, Case Western Reserve University, Cleveland, Ohio and Director of the CASE Center for AIDS Research for the generous donation of the CHME-5/HIV cell line.

Compliance with Ethical Standards

Conflict of Interests

Authors declare no conflict of interests.


  1. Aalinkeel R, Mahajan SD (2016) Neuroprotective role of galectin-1 in CNS pathophysiology associated with HIV-associated neurocognitive disorders (HAND). Neural regeneration research. Neural Regen Res 11(6):896–897PubMedPubMedCentralGoogle Scholar
  2. Almkvist J, Karlsson A (2004) Galectins as inflammatory mediators. Glycoconj J 19:575–581CrossRefPubMedGoogle Scholar
  3. Ances BM, Ellis RJ (2007) Dementia and neurocognitive disorders due to HIV-1 infection. Semin Neurol 27:86–92CrossRefPubMedGoogle Scholar
  4. Barrionuevo P, Beigier-Bompadre M, Ilarregui JM, Toscano MA, Bianco GA, Isturiz MA, Rabinovich GA (2007) A novel function for galectin-1 at the crossroad of innate and adaptive immunity: galectin-1 regulates monocyte/macrophage physiology through a nonapoptotic ERK-dependent pathway. J Immunol 178:436–445CrossRefPubMedGoogle Scholar
  5. Block ML, Zecca L, Hong JS (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8:57–69CrossRefPubMedGoogle Scholar
  6. Borgmann K, Ghorpade A (2015) HIV-1, methamphetamine and astrocytes at neuroinflammatory crossroads. Front Microbiol 6:1143CrossRefPubMedPubMedCentralGoogle Scholar
  7. Boscher C, Dennis JW, Nabi IR (2011) Glycosylation, galectins and cellular signaling. Curr Opin Cell Biol 23:383–392CrossRefPubMedGoogle Scholar
  8. Bustin SA (2002) Quantification of mRNA using real-time reverse transcription PCR (RT-PCR): trends and problems. J Mol Endocrinol 29(1):23–39Google Scholar
  9. Campbell L, Saville CR, Murray PJ, Cruickshank SM, Hardman MJ (2013) Local arginase 1 activity is required for cutaneous wound healing. J Invest Dermatol 133:2461–2470CrossRefPubMedPubMedCentralGoogle Scholar
  10. Chang C, Liao J, Kuo L (1998) Arginase modulates nitric oxide production in activated macrophages. Am J Physiol Heart Circ Physiol 274:342–348Google Scholar
  11. Chang C, Zoghi B, Liao JC, Kuo L (2000) The involvement of tyrosine kinases, cyclic AMP/protein kinase a, and p38 mitogenactivated protein kinase in IL-13-mediated arginase I induction in macrophages: its implications in IL-13-inhibited nitric oxide production. J Immunol 165:2134–2141CrossRefPubMedGoogle Scholar
  12. Chen HL, Liao F, Lin TN, Liu FT (2014) Galectins and neuroinflammation. Adv Neurobiol 9:517–542Google Scholar
  13. Cherry JD, Olschowka JA, O’Banion MK (2014) Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J Neuroinflammation 11:98CrossRefPubMedPubMedCentralGoogle Scholar
  14. Chicione LG, Stenger MR, Cui H, Calvert A, Evans RJ, Keith English B, Liu Y, Nelin LD (2011) Nitric oxide suppression of cellular proliferation depends on cationic amino acid transporter activity in cytokine-stimulated pulmonary endothelial cells. Am J Phys Lung Cell Mol Phys 300(4):L596–L604Google Scholar
  15. Correa SG, Sotomayor CE, Aoki MP, Maldonado CA, Rabinovich GA (2003) Opposite effects of galectin-1 on alternative metabolic pathways of L-arginine in resident, inflammatory, and activated macrophages. Glycobiology 13(2):119–128CrossRefPubMedGoogle Scholar
  16. Cui H, Chen B, Chicoine LG, Nelin LD (2011) Overexpression of cationic amino acid transporter-1 increases nitric oxide production in hypoxic human pulmonary microvascular endothelial cells. Clin Exp Pharmacol Physiol 38(12):796–803CrossRefPubMedPubMedCentralGoogle Scholar
  17. Dam TK, Gabius H-J, André S, Kaltner H, Lensch M, Brewer CF (2005) Galectins bind to the multivalent glycoprotein asialofetuin with enhanced affinities and a gradient of decreasing binding constants. Biochemistry 44:12564–12571CrossRefPubMedGoogle Scholar
  18. Egnaczyk GF, Pomonis JD, Schmidt JA, Rogers SD, Peters C, Ghilardi JR, Mantyh PW, Maggio JE (2003) Proteomic analysis of the reactive phenotype of astrocytes following endothelin-1 exposure. Proteomics 3:689–398CrossRefPubMedGoogle Scholar
  19. Fenn AM, Hall JCE, Gensel JC, Popovich PG, Godbout JP (2014) IL-4 signaling drives a unique arginase+/IL-1β + microglia phenotype and recruits macrophages to the inflammatory CNS: consequences of age-related deficits in IL-4Rα after traumatic spinal cord injury. J Neurosci 34:8904–8917CrossRefPubMedPubMedCentralGoogle Scholar
  20. Fischer C, Sanchez-Ruderisch H, Welzel M, Wiedenmann B, Sakai T, Andre S, Gabius HJ, Khachigian L, Detjen KM, Rosewicz S (2005) Galectin-1 interacts with the {alpha}5{beta}1 fibronectin receptor to restrict carcinoma cell growth via induction of p21 and p27. J Biol Chem 280:37266–37277CrossRefPubMedGoogle Scholar
  21. Fischer-Smith T, Rappaport J (2005) Evolving paradigms in the pathogenesis of HIV-1-associated dementia. Expert Rev Mol Med 7:1–26. doi: 10.1017/s1462399405010239 CrossRefPubMedGoogle Scholar
  22. Ghasemi M, Fatemi A (2014) Pathologic role of glial nitric oxide in adult and pediatric neuroinflammatory diseases. Neurosci Biobehav Rev 45:168–182CrossRefPubMedGoogle Scholar
  23. Glass JD, Fedor H, Wesselingh SL, McArthur JC (1995) Immunocytochemical quantitation of human immunodeficiency virus in the brain: correlations with dementia. Ann Neurol 38:755–762CrossRefPubMedGoogle Scholar
  24. Gray F, Adle-Biassette H, Brion F, Ereau T, le Maner I, Levy V, Corcket G (2000) Neuronal apoptosis in human immunodeficiency virus infection. J Neurovirol 6(Suppl 1):S38–S43PubMedGoogle Scholar
  25. Guang Luo X, Chen SD (2012) The changing phenotype of microglia from homeostasis to disease. Transl Neurosci 1:9. doi: 10.1186/2047-9158-1-9 Google Scholar
  26. Hanisch UK (2013) Functional diversity of microglia – how heterogeneous are they to begin with? Front Cell Neurosci 7:65CrossRefPubMedPubMedCentralGoogle Scholar
  27. Janabi N, Peudenier S, Héron 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(2):105–108Google Scholar
  28. Jiang W, Kim BY, Rutka JT, Chan WC (2008) Nanoparticle-mediated cellular response is size-dependent. Nat Nanotechnol 3:145–150CrossRefPubMedGoogle Scholar
  29. Kaul M, Garden GA, Lipton SA (2001) Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature 410:988–994CrossRefPubMedGoogle Scholar
  30. Kroner A, Greenhalgh AD, Zarruk JG, Passos dos Santos R, Gaestel M, David S (2014) TNF and increased intracellular iron alter macrophage polarization to a detrimental M1 phenotype in the injured spinal cord. Neuron 83:1098–1116CrossRefPubMedGoogle Scholar
  31. Lau KS, Partridge EA, Grigorian A, Silvescu CI, Reinhold VN, Demetriou M, Dennis JW (2007) Complex N-glycan number and degree of branching cooperate to regulate cell proliferation and differentiation. Cell 129:123–134CrossRefPubMedGoogle Scholar
  32. Lee RT, Lee YC (2000) Affinity enhancement by multivalent lectin–carbohydrate interaction. Glycoconj J 17:543–551CrossRefPubMedGoogle Scholar
  33. Leffler H, Carlsson S, Hedlund M, Qian Y, Poirier F (2004) Introduction to galectins. Glycocon 19:433–440CrossRefGoogle Scholar
  34. Louboutin J-P, Strayer D (2014) Role of oxidative stress in HIV-1-associated neurocognitive disorder and protection by Gene delivery of antioxidant enzymes. Antioxidants 3(4):770–797CrossRefPubMedPubMedCentralGoogle Scholar
  35. Lull ME, Block ML (2010) Microglial activation & chronic neurodegeneration. Neurotherapeutics. 7(4):354–365Google Scholar
  36. Lutomski D, Fouillit M, Bourin P, Mellottee D, Denize N, Pontet M, Bladier D, Caron M, Joubert-Caron R (1997) Externalization and binding of galectin-1 on cell surface of K562 cells upon erythroid differentiation. Glycobiology 7:1193–1199CrossRefPubMedGoogle Scholar
  37. McGraw J, Gaudet AD, Oschipok LW, Kadoya T, Horie H, Steeves JD, Tetzlaff W, Ramer MS (2005) Regulation of neuronal and glial galectin-1 expression by peripheral and central axotomy of rat primary afferent neurons. Exp Neurol 195:103–114CrossRefPubMedGoogle Scholar
  38. Mercier S, St-Pierre C, Pelletier I, Ouellet M, Tremblay MJ, Sato S (2008) Galectin-1 promotes HIV-1 infectivity in macrophages through stabilization of viral adsorption. Virology 371:121–129CrossRefPubMedGoogle Scholar
  39. Miró-Mur F, Pérez-de-Puig I, Ferrer-Ferrer M, Urra X, Justicia C, Chamorro A, Planas AM (2015) Immature monocytes recruited to the ischemic mouse brain differentiate into macrophages with features of alternative activation. Brain Behav Immun 48:18–33Google Scholar
  40. Morris SM (2007) Arginine metabolism: boundaries of our knowledge. J Nutr 137:1602S–1609SPubMedGoogle Scholar
  41. Munder M (2009) Arginase: an emerging key player in the mammalian immune system. Br J Pharmacol 158:638–651CrossRefPubMedPubMedCentralGoogle Scholar
  42. Nath A, Conant K, Chen P, Scott C, Major EO (1999) Transient exposure to HIV-1 tat protein results in cytokine production in macrophages and astrocytes. A hit and run phenomenon. J Biol Chem 274:17098–17102CrossRefPubMedGoogle Scholar
  43. Nieves CJ Jr, Langkamp-Henken B (2002) Arginine and immunity: a unique perspective. Biomed Pharmacother 56:471–482CrossRefPubMedGoogle Scholar
  44. Nonaka M, Fukuda M (2012) Galectin-1 for neuroprotection? Immunity 37(2):187–189CrossRefPubMedGoogle Scholar
  45. Ouellet MS, Pelletier I, Bounou S, Roy J, Hirabayashi J, Sato S, Tremblay MJ (2005) Galectin-1 acts as a soluble host factor that promotes HIV-1 infectivity through stabilization of virus attachment to host cells. J Immunol 174:4120–4126CrossRefPubMedGoogle Scholar
  46. Ouellet M, St-Pierre C, Tremblay MJ, Sato S (2015) Effect of galectins on viral transmission. Methods Mol Biol 1207:397–420CrossRefPubMedGoogle Scholar
  47. Parikh NU, Aalinkeel R, Reynolds JL, Nair BB, Sykes DE, Mammen MJ, Schwartz SA, Mahajan SD (2015) Galectin-1 suppresses methamphetamine induced neuroinflammation in human brain microvascular endothelial cells: Neuroprotective role in maintaining blood brain barrier integrity. Brain Res 1624:175–187Google Scholar
  48. Partridge EA, Le Roy C, Di Guglielmo GM, Pawling J, Cheung P, Granovsky M, Nabi IR, Wrana JL, Dennis JW (2004) Regulation of cytokine receptors by Golgi N-glycan processing and endocytosis. Science 306:120–124CrossRefPubMedGoogle Scholar
  49. Peranzoni E, Marigo I, Dolcetti L, Ugel S, Sonda N, Taschin E, Mantelli B, Bronte V, Zanovello P (2007) Role of arginine metabolism in immunity and immunopathology. Immunobiology 212:795–812CrossRefPubMedGoogle Scholar
  50. Pesce JT, Ramalingam TR, Mentink-Kane MM, Wilson MS, El Kasmi KC, Smith AM, Thompson RW, Cheever AW, Murray PJ, Wynn TA (2009) Arginase-1 expressing macrophages suppress Th2 cytokine driven inflammation and fibrosis. PLoS Pathog 5:e1000371CrossRefPubMedPubMedCentralGoogle Scholar
  51. Qu WS, Wang YH, Ma JF, Tian DS, Zhang Q, Pan DJ, Yu ZY, Xie MJ, Wang JP, Wang W (2011) Galectin-1 attenuates astrogliosis-associated injuries and improves recovery of rats following focal cerebral ischemia. J Neurochem 116(2):217–226CrossRefPubMedGoogle Scholar
  52. Radonić A, Thulke S, Mackay IM, Landt O, Siegert W, Nitsche A (2004) Guideline to reference gene selection for quantitative real-time PCR. Biochem Biophys Res Commun 313(4):856–862Google Scholar
  53. Rath M, Müller I, Kropf P, Closs EI, Munder M (2014) Metabolism via arginase or nitric oxide synthase: two competing arginine pathways in macrophages. Front Immunol 5:532CrossRefPubMedPubMedCentralGoogle Scholar
  54. Reynolds JL, Mahajan SD, Sykes D, Nair MP (2006) Heroin-induces differential protein expression by normal human astrocytes (NHA). Am J Infect Dis 2(2):49–57CrossRefPubMedPubMedCentralGoogle Scholar
  55. Reynolds JL, Mahajan SD, Sykes DE, Schwartz SA, Nair MP (2007) Proteomic analyses of methamphetamine (METH)-induced differential protein expression by immature dendritic cells (IDC). Biochim Biophys Acta 1774(4):433–442CrossRefPubMedPubMedCentralGoogle Scholar
  56. Reynolds JL, Law WC, Mahajan SD, Aalinkeel R, Nair B, Sykes DE, Mammen MJ, Yong KT, Hui R, Prasad PN, Schwartz SA (2012a) Morphine and galectin-1 modulate HIV-1 infection of human monocyte-derived macrophages. J Immunol 188(8):3757–3765CrossRefPubMedPubMedCentralGoogle Scholar
  57. Reynolds JL, Law WC, Mahajan SD, Aalinkeel R, Nair B, Sykes DE, Yong KT, Hui R, Prasad PN, Schwartz SA (2012b) Nanoparticle based galectin-1 gene silencing, implications in methamphetamine regulation of HIV-1 infection in monocyte derived macrophages. J NeuroImmune Pharmacol 7(3):673–685CrossRefPubMedPubMedCentralGoogle Scholar
  58. Rezai-Zadeh K, Gate D, Town T (2009) CNS infiltration of peripheral immune cells: D-day for neurodegenerative disease? J NeuroImmune Pharmacol 4(4):462–475. doi: 10.1007/s11481-009-9166-2 CrossRefPubMedPubMedCentralGoogle Scholar
  59. Rock RB, Gekker G, Hu S, Sheng WS, Cheeran M, Lokensgard JR, Peterson PK (2004) Role of microglia in central nervous system infections. Clin Microbiol Rev 17(4):942–964CrossRefPubMedPubMedCentralGoogle Scholar
  60. Rojo AI, McBean G, Cindric M, Egea J, López MG, Rada P, … Cuadrado A (2014) Redox control of microglial function: molecular mechanisms and functional significance. Antioxid Redox Signal, 21(12):1766–1801Google Scholar
  61. Saijo K, Glass CK (2011) Microglial cell origin and phenotypes in health and disease. Nat Rev Immunol 11:775–787. doi: 10.1038/nri3086 CrossRefPubMedGoogle Scholar
  62. Sato S, Ouellet M, St-Pierre C, Tremblay MJ (2012) Glycans, galectins, and HIV-1 infection. Ann N Y Acad Sci 1253:133–148CrossRefPubMedGoogle Scholar
  63. Schnell G, Price RW, Swanstrom R, Spudich S (2010) Compartmentalization and clonal amplification of HIV-1 variants in the cerebrospinal fluid during primary infection. J Virol 84:2395–2407. doi: 10.1128/JVI.01863-09 CrossRefPubMedGoogle Scholar
  64. Sonoki T, Nagasaki A, Gotoh T, Takiguchi M, Takeya M, Matsuzaki H, Mori M (1997) Co-induction of nitric-oxide synthase and arginase I in cultured rat peritoneal macrophages and rat tissues in vivo by lipopolysaccharide. J Biol Chem 272:3689–3693CrossRefPubMedGoogle Scholar
  65. Starossom SC, Mascanfroni ID, Imitola J, Cao L, Raddassi K, Hernandez S, Bassil R, Croci DO, Cerliani JP, Delacour D, Wang Y, Elyaman W, Khoury SJ, Rabinovich GA (2012) Galectin-1 deactivates classically-activated microglia and protects from inflammation-induced neurodegeneration. Immunity 37(2):249–263CrossRefPubMedPubMedCentralGoogle Scholar
  66. St-Pierre C, Ouellet M, Tremblay MJ, Sato S (2010) Galectin-1 and HIV-. Methods Enzymol 480:267–294Google Scholar
  67. St-Pierre C, Ouellet M, Giguère D, Ohtake R, Roy R, Sato S, Tremblay MJ (2012) Galectin-1-specific inhibitors as a new class of compounds to treat HIV-1 infection. Antimicrob Agents Chemother 56(1):154–162CrossRefPubMedPubMedCentralGoogle Scholar
  68. Sturdevant CB, Joseph SB, Schnell G, Price RW, Swanstrom R, Spudich S (2015) Compartmentalized replication of R5 T cell-tropic HIV-1 in the central nervous system early in the course of infection. PLoS Pathog 11(3):e1004720. doi: 10.1371/journal.ppat.1004720 CrossRefPubMedPubMedCentralGoogle Scholar
  69. Tang Y, Le W (2016) Differential roles of M1 and M2 microglia in neurodegenerative diseases. Mol Neurobiol 53:1181–1194CrossRefPubMedGoogle Scholar
  70. Valcour V, Chalermchai T, Sailasuta N, Marovich M, Lerdlum S et al (2012) Central nervous system viral invasion and inflammation during acute HIV infection. J Infect Dis 206:275–282CrossRefPubMedPubMedCentralGoogle Scholar
  71. Wada M, Ono S, Kadoya T, Kawanami T, Kurita K, Kato T (2003) Decreased galectin-1 immunoreactivity of the skin in amyotrophic lateral sclerosis. J Neurol Sci 208:67–70CrossRefPubMedGoogle Scholar
  72. Wires ES, Alvarez D, Dobrowolski C, Wang Y, Morales M, Karn J, Harvey BK (2012) Methamphetamine activates nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and induces human immunodeficiency virus (HIV) transcription in human microglial cells. J Neurovirol 18(5):400–410CrossRefPubMedPubMedCentralGoogle Scholar
  73. Zani BG, Bohlen HG (2005) Transport of extracellular l-arginine via cationic amino acid transporter is required during in vivo endothelial nitric oxide production. Am J Physiol Heart Circ Physiol 289(4):H1381–H1390CrossRefPubMedGoogle Scholar
  74. Zanon CF, Sonehara NM, Girol AP, Gil CD, Oliani SM (2015) Protective effects of the galectin-1 protein on in vivo and in vitro models of ocular inflammation. Mol Vis 21:1036–1050Google Scholar
  75. Zhang N, Deng J, Wu F, Lu X, Huang L, Zhao M (2016) Expression of arginase I and inducible nitric oxide synthase in the peripheral blood and lymph nodes of HIV-positive patients. Mol Med Rep 13(1):731–743. doi: 10.3892/mmr.2015.4601 PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Ravikumar Aalinkeel
    • 1
  • Courtney S. Mangum
    • 1
  • Eliane Abou-Jaoude
    • 1
  • Jessica L. Reynolds
    • 1
  • Maixian Liu
    • 1
  • Karin Sundquist
    • 1
  • Neil U. Parikh
    • 1
  • Lee D. Chaves
    • 2
  • Manoj J. Mammen
    • 1
  • Stanley A. Schwartz
    • 1
  • Supriya D. Mahajan
    • 1
    Email author
  1. 1.Department of Medicine, Division of Allergy, Immunology & Rheumatology, 6074 UB’s Clinical and Translational Research CenterState University of New York at BuffaloBuffaloUSA
  2. 2.Department of Medicine, Division of Nephrology, UB Clinical and Translational Research CenterSUNY University at BuffaloBuffaloUSA

Personalised recommendations