Insulin-like growth factor 1 and 2 (IGF1, IGF2) expression in human microglia: differential regulation by inflammatory mediators

Journal of Neuroinflammation

Sunhee C Lee¹  Namjong Choi¹  Leandra Derico¹  Meng-Liang Zhao¹  Hyeon-Sook Suh¹ 

[1] Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA

关键词: Microglia;    LPS;    Inflammation;    IGF2;    IGF1;    Human;    HIV;    Growth factors;    Cytokines;    Brain;   

Others  :  1160012
DOI  :  10.1186/1742-2094-10-37

 received in 2012-11-09, accepted in 2013-01-03,  发布年份 2013

【 摘 要 】

Background

Recent studies in experimental animals show that insulin-like growth factor 1 (IGF1) plays a trophic role during development and tissue injury and that microglia are important sources of IGF1. However, little information is available regarding the expression, regulation, and function of IGF1 and related proteins in human brain cells. In the current study, we examined the expression of IGF1 and IGF2 in human microglia in vivo and in vitro.

Methods

Expression of IGF1 and IGF2 was examined by immunohistochemistry in post-mortem human brain sections derived from HIV+ and HIV− brains. In primary cultures of human fetal microglia, IGF1 and IGF2 mRNA and protein expression was examined by Q-PCR, ELISA, and Western blot analysis. Additionally, the role of IGF1 and IGF2 in neuroprotection was examined in primary human neuronal glial cultures.

Results

Immunohistochemistry of human brain tissues showed that nonparenchymal cells (vessels and meninges), as well as parenchymal microglia and macrophages were positive for IGF1, in both HIV encephalitis and control brains, while IGF2 was undetectable. Cultured microglia expressed IGF1 mRNA and produced pg/ml levels of IGF1 protein; this was significantly suppressed by proinflammatory mediators, such as lipopolysaccharide (LPS), poly(I:C), and IFNγ. The Th2 cytokines IL-4 and IL-13 had no significant effect, but the cAMP analog (dibutyryl cAMP) significantly increased IGF1 production. In contrast, microglial IGF2 mRNA and protein (determined by Western blot) were upregulated by LPS. IGF1 receptor (IGF1R) immunoreactivity was predominantly expressed by neurons, and both IGF1 and IGF2 significantly protected neurons from cytokine (IL-1/IFNγ) induced death.

Conclusions

Our study in human brain tissues and cells indicates that microglia are important sources of neurotrophic growth factors IGF1 and IGF2, and that microglial activation phenotypes can influence the growth factor expression. Importantly, our results suggest that chronic neuroinflammation and upregulation of proinflammatory cytokines could lead to neurodegeneration by suppressing the production of microglia-derived neuronal growth factors, such as IGF1.

【 授权许可】

   
2013 Suh et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

【 参考文献 】

• [1]Hanisch UK, Kettenmann H: Microglia: active sensor and versatile effector cells in the normal and pathologic brain. Nat Neurosci 2007, 10:1387-1394.
• [2]Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin ML, Gan WB: ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 2005, 8:752-758.
• [3]Gowing G, Vallieres L, Julien JP: Mouse model for ablation of proliferating microglia in acute CNS injuries. Glia 2006, 53:331-337.
• [4]Lalancette-Hebert M, Gowing G, Simard A, Weng YC, Kriz J: Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. J Neurosci 2007, 27:2596-2605.
• [5]Neumann J, Sauerzweig S, Ronicke R, Gunzer F, Dinkel K, Ullrich O, Gunzer M, Reymann KG: Microglia cells protect neurons by direct engulfment of invading neutrophil granulocytes: a new mechanism of CNS immune privilege. J Neurosci 2008, 28:5965-5975.
• [6]Butovsky O, Landa G, Kunis G, Ziv Y, Avidan H, Greenberg N, Schwartz A, Smirnov I, Pollack A, Jung S, Schwartz M: Induction and blockage of oligodendrogenesis by differently activated microglia in an animal model of multiple sclerosis. J Clin Invest 2006, 116:905-915.
• [7]Ajami B, Bennett JL, Krieger C, McNagny KM, Rossi FM: Infiltrating monocytes trigger EAE progression, but do not contribute to the resident microglia pool. Nat Neurosci 2011, 14:1142-1149.
• [8]Ransohoff RM: Microglia and monocytes: ’tis plain the twain meet in the brain. Nat Neurosci 2011, 14:1098-1100.
• [9]Gordon S: Alternative activation of macrophages. Nat Rev Immunol 2003, 3:23-35.
• [10]Van Ginderachter JA, Movahedi K, Hassanzadeh GG, Meerschaut S, Beschin A, Raes G, De BP: Classical and alternative activation of mononuclear phagocytes: picking the best of both worlds for tumor promotion. Immunobiology 2006, 211:487-501.
• [11]Suh HS, Choi N, Tarassishin L, Lee SC: Regulation of progranulin expression in human microglia and proteolysis of progranulin by Matrix Metalloproteinase-12 (MMP-12). PLoS One 2012, 7:e35115.
• [12]Ahmed Z, Mackenzie IR, Hutton ML, Dickson DW: Progranulin in frontotemporal lobar degeneration and neuroinflammation. J Neuroinflammation 2007, 4:7. BioMed Central Full Text
• [13]Batchelor PE, Porritt MJ, Martinello P, Parish CL, Liberatore GT, Donnan GA, Howells DW: Macrophages and microglia produce local trophic gradients that stimulate axonal sprouting toward but not beyond the wound edge. Mol Cell Neurosci 2002, 21:436-453.
• [14]Denis M: Human monocytes/macrophages: NO or no NO? J Leukoc Biol 1994, 55:682-684.
• [15]Raes G, Van den BR, De BP, Ghassabeh GH, Scotton C, Locati M, Mantovani A, Sozzani S: Arginase-1 and Ym1 are markers for murine, but not human, alternatively activated myeloid cells. J Immunol 2005, 174:6561-6562.
• [16]Denley A, Cosgrove LJ, Booker GW, Wallace JC, Forbes BE: Molecular interactions of the IGF system. Cytokine Growth Factor Rev 2005, 16:421-439.
• [17]Carson MJ, Behringer RR, Brinster RL, McMorris FA: Insulin-like growth factor I increases brain growth and central nervous system myelination in transgenic mice. Neuron 1993, 10:729-740.
• [18]Ye P, Li L, Richards RG, DiAugustine RP, D’Ercole AJ: Myelination is altered in insulin-like growth factor-I null mutant mice. J Neurosci 2002, 22:6041-6051.
• [19]Camacho-Hubner C, Woods KA, Clark AJ, Savage MO: Insulin-like growth factor (IGF)-I gene deletion. Rev Endocr Metab Disord 2002, 3:357-361.
• [20]Fernandez AM, Torres-Aleman I: The many faces of insulin-like peptide signalling in the brain. Nat Rev Neurosci 2012, 13:225-239.
• [21]Duan C: Specifying the cellular responses to IGF signals: roles of IGF-binding proteins. J Endocrinol 2002, 175:41-54.
• [22]Bondy CA, Cheng CM: Signaling by insulin-like growth factor 1 in brain. Eur J Pharmacol 2004, 490:25-31.
• [23]Hawkes C, Kar S: The insulin-like growth factor-II/mannose-6-phosphate receptor: structure, distribution and function in the central nervous system. Brain Res Brain Res Rev 2004, 44:117-140.
• [24]Carro E, Trejo JL, Gomez-Isla T, LeRoith D, Torres-Aleman I: Serum insulin-like growth factor I regulates brain amyloid-beta levels. Nat Med 2002, 8:1390-1397.
• [25]Russo VC, Gluckman PD, Feldman EL, Werther GA: The insulin-like growth factor system and its pleiotropic functions in brain. Endocr Rev 2005, 26:916-943.
• [26]Alvarez A, Cacabelos R, Sanpedro C, Garcia-Fantini M, Aleixandre M: Serum TNF-alpha levels are increased and correlate negatively with free IGF-I in Alzheimer disease. Neurobiol Aging 2007, 28:533-536.
• [27]Congote LF: Monitoring insulin-like growth factors in HIV infection and AIDS. Clin Chim Acta 2005, 361:30-53.
• [28]Strickler HD, Fazzari M, Kovacs A, Isasi C, Napolitano LA, Minkoff H, Gange S, Young M, Sharp GB, Kaplan RC, Cohen M, Gunter MJ, Harris TG, Yu H, Schoenbaum E, Landay AL, Anastos K: Associations of insulin-like growth factor (IGF)-I and IGF-binding protein-3 with HIV disease progression in women. J Infect Dis 2008, 197:319-327.
• [29]Suh HS, Cosenza-Nashat M, Choi N, Zhao ML, Li JF, Pollard JW, Jirtle RL, Goldstein H, Lee SC: Insulin-like growth factor 2 receptor is an IFNgamma-inducible microglial protein that facilitates intracellular HIV replication: implications for HIV-induced neurocognitive disorders. Am J Pathol 2010, 177:2446-2458.
• [30]Cosenza-Nashat MA, Kim MO, Zhao ML, Suh HS, Lee SC: CD45 isoform expression in microglia and inflammatory cells in HIV-1 encephalitis. Brain Pathol 2006, 16:256-265.
• [31]Cosenza MA, Zhao ML, Si Q, Lee SC: Human brain parenchymal microglia express CD14 and CD45 and are productively infected by HIV-1 in HIV-1 encephalitis. Brain Pathol 2002, 12:442-455.
• [32]Huang GS, Brouwer-Visser J, Ramirez MJ, Kim CH, Hebert TM, Lin J, Arias-Pulido H, Qualls CR, Prossnitz ER, Goldberg GL, Smith HO, Horwitz SB: Insulin-like growth factor 2 expression modulates Taxol resistance and is a candidate biomarker for reduced disease-free survival in ovarian cancer. Clin Cancer Res 2010, 16:2999-3010.
• [33]Suh HS, Kim MO, Lee SC: Inhibition of granulocyte-macrophage colony-stimulating factor signaling and microglial proliferation by anti-CD45RO: role of Hck tyrosine kinase and phosphatidylinositol 3-kinase/Akt. J Immunol 2005, 174:2712-2719.
• [34]Lee SC, Liu W, Brosnan CF, Dickson DW: Characterization of primary human fetal dissociated central nervous system cultures with an emphasis on microglia. Lab Invest 1992, 67:465-476.
• [35]Suh HS, Zhao ML, Rivieccio M, Choi S, Connolly E, Zhao Y, Takikawa O, Brosnan CF, Lee SC: Astrocyte indoleamine 2,3-dioxygenase is induced by the TLR3 ligand poly(I:C): mechanism of induction and role in antiviral response. J Virol 2007, 81:9838-9850.
• [36]Rivieccio MA, Suh HS, Zhao Y, Zhao ML, Chin KC, Lee SC, Brosnan CF: TLR3 ligation activates an antiviral response in human fetal astrocytes: a role for viperin/cig5. J Immunol 2006, 177:4735-4741.
• [37]Downen M, Amaral TD, Hua LL, Zhao ML, Lee SC: Neuronal death in cytokine-activated primary human brain cell culture: role of tumor necrosis factor-alpha. Glia 1999, 28:114-127.
• [38]Krause D, Suh HS, Tarassishin L, Cui QL, Durafourt BA, Choi N, Bauman A, Cosenza-Nashat M, Antel JP, Zhao ML, Lee SC: The tryptophan metabolite 3-hydroxyanthranilic acid plays anti-inflammatory and neuroprotective roles during inflammation: role of hemeoxygenase-1. Am J Pathol 2011, 179:1360-1372.
• [39]Tarassishin L, Suh HS, Lee SC: Interferon regulatory factor 3 plays an anti-inflammatory role in microglia by activating the PI3K/Akt pathway. J Neuroinflammation 2011, 8:187. BioMed Central Full Text
• [40]Siddappa R, Martens A, Doorn J, Leusink A, Olivo C, Licht R, van Rijn L, Gaspar C, Fodde R, Janssen F, van Blitterswijk C, de Boer J: cAMP/PKA pathway activation in human mesenchymal stem cells in vitro results in robust bone formation in vivo. Proc Natl Acad Sci USA 2008, 105:7281-7286.
• [41]Fournier T, Riches DW, Winston BW, Rose DM, Young SK, Noble PW, Lake FR, Henson PM: Divergence in macrophage insulin-like growth factor-I (IGF-I) synthesis induced by TNF-alpha and prostaglandin E2. J Immunol 1995, 155:2123-2133.
• [42]Bondy C, Werner H, Roberts CT Jr, LeRoith D: Cellular pattern of type-I insulin-like growth factor receptor gene expression during maturation of the rat brain: comparison with insulin-like growth factors I and II. Neuroscience 1992, 46:909-923.
• [43]Han VK, D’Ercole AJ, Lund PK: Cellular localization of somatomedin (insulin-like growth factor) messenger RNA in the human fetus. Science 1987, 236:193-197.
• [44]Haselbacher GK, Schwab ME, Pasi A, Humbel RE: Insulin-like growth factor II (IGF II) in human brain: regional distribution of IGF II and of higher molecular mass forms. Proc Natl Acad Sci USA 1985, 82:2153-2157.
• [45]Komoly S, Hudson LD, Webster HD, Bondy CA: Insulin-like growth factor I gene expression is induced in astrocytes during experimental demyelination. Proc Natl Acad Sci USA 1992, 89:1894-1898.
• [46]Lee WH, Clemens JA, Bondy CA: Insulin-like growth factors in the response to cerebral ischemia. Mol Cell Neurosci 1992, 3:36-43.
• [47]Selvamani A, Sathyan P, Miranda RC, Sohrabji F: An antagomir to microRNA Let7f promotes neuroprotection in an ischemic stroke model. PLoS One 2012, 7:e32662.
• [48]O’Donnell SL, Frederick TJ, Krady JK, Vannucci SJ, Wood TL: IGF-I and microglia/macrophage proliferation in the ischemic mouse brain. Glia 2002, 39:85-97.
• [49]Rotwein P, Burgess SK, Milbrandt JD, Krause JE: Differential expression of insulin-like growth factor genes in rat central nervous system. Proc Natl Acad Sci USA 1988, 85:265-269.
• [50]Kaur C, Sivakumar V, Dheen ST, Ling EA: Insulin-like growth factor I and II expression and modulation in amoeboid microglial cells by lipopolysaccharide and retinoic acid. Neuroscience 2006, 138:1233-1244.
• [51]Kihira T, Suzuki A, Kubo T, Miwa H, Kondo T: Expression of insulin-like growth factor-II and leukemia inhibitory factor antibody immunostaining on the ionized calcium-binding adaptor molecule 1-positive microglias in the spinal cord of amyotrophic lateral sclerosis patients. Neuropathology 2007, 27:257-268.
• [52]Wynes MW, Riches DW: Induction of macrophage insulin-like growth factor-I expression by the Th2 cytokines IL-4 and IL-13. J Immunol 2003, 171:3550-3559.
• [53]Arkins S, Rebeiz N, Brunke-Reese DL, Biragyn A, Kelley KW: Interferon-gamma inhibits macrophage insulin-like growth factor-I synthesis at the transcriptional level. Mol Endocrinol 1995, 9:350-360.
• [54]Zhou Y, Zhang Y, Li J, Lv F, Zhao Y, Duan D, Xu Q: A comprehensive study on long-term injury to nigral dopaminergic neurons following intracerebroventricular injection of lipopolysaccharide in rats. J Neurochem 2012, 123:771-780.
• [55]Kelley KW: From hormones to immunity: the physiology of immunology. Brain Behav Immun 2004, 18:95-113.
• [56]Thissen JP, Verniers J: Inhibition by interleukin-1 beta and tumor necrosis factor-alpha of the insulin-like growth factor I messenger ribonucleic acid response to growth hormone in rat hepatocyte primary culture. Endocrinology 1997, 138:1078-1084.
• [57]Thomas MJ, Umayahara Y, Shu H, Centrella M, Rotwein P, McCarthy TL: Identification of the cAMP response element that controls transcriptional activation of the insulin-like growth factor-I gene by prostaglandin E2 in osteoblasts. J Biol Chem 1996, 271:21835-21841.
• [58]Hatey F, Langlois I, Mulsant P, Bonnet A, Benne F, Gasser F: Gonadotropins induce accumulation of insulin-like growth factor I mRNA in pig granulosa cells in vitro. Mol Cell Endocrinol 1992, 86:205-211.
• [59]Feinstein DL, Heneka MT, Gavrilyuk V, Dello RC, Weinberg G, Galea E: Noradrenergic regulation of inflammatory gene expression in brain. Neurochem Int 2002, 41:357-365.
• [60]Lee SC, Collins M, Vanguri P, Shin ML: Glutamate differentially inhibits the expression of class II MHC antigens on astrocytes and microglia. J Immunol 1992, 148:3391-3397.
• [61]Zarrilli R, Bruni CB, Riccio A: Multiple levels of control of insulin-like growth factor gene expression. Mol Cell Endocrinol 1994, 101:R1-R14.
• [62]Bilic E, Bilic E, Rudan I, Kusec V, Zurak N, Delimar D, Zagar M: Comparison of the growth hormone, IGF-1 and insulin in cerebrospinal fluid and serum between patients with motor neuron disease and healthy controls. Eur J Neurol 2006, 13:1340-1345.
• [63]Kang YJ, Digicaylioglu M, Russo R, Kaul M, Achim CL, Fletcher L, Masliah E, Lipton SA: Erythropoietin plus insulin-like growth factor-I protects against neuronal damage in a murine model of human immunodeficiency virus-associated neurocognitive disorders. Ann Neurol 2010, 68:342-352.
• [64]Ying WJ, Peruzzi F, Lassak A, Del VL, Radhakrishnan S, Rappaport J, Khalili K, Amini S, Reiss K: Neuroprotective effects of IGF-I against TNFalpha-induced neuronal damage in HIV-associated dementia. Virology 2003, 305:66-76.
• [65]Bellini MJ, Herenu CB, Goya RG, Garcia-Segura LM: Insulin-like growth factor-I gene delivery to astrocytes reduces their inflammatory response to lipopolysaccharide. J Neuroinflammation 2011, 8:21. BioMed Central Full Text
• [66]Chen DY, Stern SA, Garcia-Osta A, Saunier-Rebori B, Pollonini G, Bambah-Mukku D, Blitzer RD, Alberini CM: A critical role for IGF-II in memory consolidation and enhancement. Nature 2011, 469:491-497.
• [67]Agis-Balboa RC, Arcos-Diaz D, Wittnam J, Govindarajan N, Blom K, Burkhardt S, Haladyniak U, Agbemenyah HY, Zovoilis A, Salinas-Riester G, Opitz L, Sananbenesi F, Fischer A: A hippocampal insulin-growth factor 2 pathway regulates the extinction of fear memories. EMBO J 2011, 30:4071-4083.