Poly(I:C) promotes TNFα/TNFR1-dependent oligodendrocyte death in mixed glial cultures

Journal of Neuroinflammation

Jianrong Li¹  Andrew J Steelman¹ 

[1] Department of Veterinary Integrative BioSciences, Texas A&M University, College Station, Texas,77843, USA

关键词: astrocytes;    microglia activation;    TNFα;    TLR;    oligodendrocyte death;    poly(I:C);   

Others  :  1213216
DOI  :  10.1186/1742-2094-8-89

 received in 2011-02-26, accepted in 2011-08-03,  发布年份 2011

【 摘 要 】

Background

Activation of glial cells via toll-like receptors (TLRs) and other intracellular pathogen recognition receptors promotes the release of potentially toxic acute phase reactants such as TNFα and nitric oxide into the extracellular space. As such, prolonged glial activation, as is thought to occur during a persistent viral infection of the CNS, may contribute to both neurodegeneration and demyelination. However, the effects of virus-induced glial activation on oligodendrocytes are not fully understood.

Method

To determine the effects of glial activation on oligodendrocyte viability we treated primary glial cultures isolated from neonatal rats or mice with the RNA viral mimic poly(I:C) and in some cases other TLR ligands. TLR3 expression was determined by western blot. Cytokine levels were measured by RT-PCR, ELISA, and intracellular cytokine staining. Oligodendrocyte precursor (preOL) viability was determined by Alamar blue assays and immunocytochemistry.

Result

Stimulation of mixed glial cultures with poly(I:C) resulted in microglia activation, TNFα production and preOL toxicity. This toxic effect of poly(I:C) was indirect as it failed to affect preOL viability in pure cultures despite the fact that preOLs express TLR3. Poly(I:C)-induced loss of preOLs was abolished in TNFα or TNFR1 deficient mixed glial cultures, suggesting that TNFα/TNFR1 signaling is required for poly(I:C) toxicity. Furthermore, although both microglia and astrocytes express functional TLR3, only microglia produced TNFα in culture. Consistent with these findings, other TLR agonists similarly triggered TNFα production and preOL toxicity in mixed glial cultures.

Conclusion

Activation of microglia by poly(I:C) promotes TNFα/TNFR1-dependent oligodendroglial cell death. These data indicate that during an ongoing viral infection of the CNS, microglial TNFα may be detrimental to oligodendrocytes.

【 授权许可】

   
2011 Steelman and Li; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]Galea I, Bechmann I, Perry VH: What is immune privilege (not)? Trends Immunol 2007, 28:12-18.
• [2]Nair A, Frederick TJ, Miller SD: Astrocytes in multiple sclerosis: a product of their environment. Cell Mol Life Sci 2008, 65:2702-2720.
• [3]Ransohoff RM, Cardona AE: The myeloid cells of the central nervous system parenchyma. Nature 2010, 468:253-262.
• [4]Ransohoff RM, Perry VH: Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol 2009, 27:119-145.
• [5]Williams A, Piaton G, Lubetzki C: Astrocytes--friends or foes in multiple sclerosis? Glia 2007, 55:1300-1312.
• [6]Takeuchi O, Akira S: Pattern recognition receptors and inflammation. Cell 2010, 140:805-820.
• [7]Bsibsi M, Persoon-Deen C, Verwer RW, Meeuwsen S, Ravid R, Van Noort JM: Toll-like receptor 3 on adult human astrocytes triggers production of neuroprotective mediators. Glia 2006, 53:688-695.
• [8]Bsibsi M, Bajramovic JJ, Vogt MH, van Duijvenvoorden E, Baghat A, Persoon-Deen C, Tielen F, Verbeek R, Huitinga I, Ryffel B, et al.: The microtubule regulator stathmin is an endogenous protein agonist for TLR3. J Immunol 2010, 184:6929-6937.
• [9]Furr SR, Moerdyk-Schauwecker M, Grdzelishvili VZ, Marriott I: RIG-I mediates nonsegmented negative-sense RNA virus-induced inflammatory immune responses of primary human astrocytes. Glia 2010, 58:1620-1629.
• [10]Furr SR, Chauhan VS, Sterka D Jr, Grdzelishvili V, Marriott I: Characterization of retinoic acid-inducible gene-I expression in primary murine glia following exposure to vesicular stomatitis virus. J Neurovirol 2008, 14:503-513.
• [11]De Miranda J, Yaddanapudi K, Hornig M, Lipkin WI: Astrocytes recognize intracellular polyinosinic-polycytidylic acid via MDA-5. FASEB J 2009, 23:1064-1071.
• [12]Lathia JD, Okun E, Tang SC, Griffioen K, Cheng A, Mughal MR, Laryea G, Selvaraj PK, ffrench-Constant C, Magnus T, et al.: Toll-like receptor 3 is a negative regulator of embryonic neural progenitor cell proliferation. J Neurosci 2008, 28:13978-13984.
• [13]Peltier DC, Simms A, Farmer JR, Miller DJ: Human neuronal cells possess functional cytoplasmic and TLR-mediated innate immune pathways influenced by phosphatidylinositol-3 kinase signaling. J Immunol 2010, 184:7010-7021.
• [14]Prehaud C, Megret F, Lafage M, Lafon M: Virus infection switches TLR-3-positive human neurons to become strong producers of beta interferon. J Virol 2005, 79:12893-12904.
• [15]Bsibsi M, Ravid R, Gveric D, van Noort JM: Broad expression of Toll-like receptors in the human central nervous system. J Neuropathol Exp Neurol 2002, 61:1013-1021.
• [16]Li J, Liu Y, Zhang X: Murine Coronavirus Induces Type I Interferon in Oligodendrocytes Through Recognition by RIG-I and MDA5. J Virol 2010, 84:6472-6482.
• [17]Lehnardt S, Lachance C, Patrizi S, Lefebvre S, Follett PL, Jensen FE, Rosenberg PA, Volpe JJ, Vartanian T: The toll-like receptor TLR4 is necessary for lipopolysaccharide-induced oligodendrocyte injury in the CNS. J Neurosci 2002, 22:2478-2486.
• [18]Deleidi M, Hallett PJ, Koprich JB, Chung CY, Isacson O: The toll-like receptor-3 agonist polyinosinic:polycytidylic acid triggers nigrostriatal dopaminergic degeneration. J Neurosci 2010, 30:16091-16101.
• [19]Felts PA, Woolston AM, Fernando HB, Asquith S, Gregson NA, Mizzi OJ, Smith KJ: Inflammation and primary demyelination induced by the intraspinal injection of lipopolysaccharide. Brain 2005, 128:1649-1666.
• [20]Fitch MT, Doller C, Combs CK, Landreth GE, Silver J: Cellular and molecular mechanisms of glial scarring and progressive cavitation: in vivo and in vitro analysis of inflammation-induced secondary injury after CNS trauma. J Neurosci 1999, 19:8182-8198.
• [21]Popovich PG, Guan Z, McGaughy V, Fisher L, Hickey WF, Basso DM: The neuropathological and behavioral consequences of intraspinal microglial/macrophage activation. J Neuropathol Exp Neurol 2002, 61:623-633.
• [22]Fazakerley JK, Walker R: Virus demyelination. J Neurovirol 2003, 9:148-164.
• [23]Munz C, Lunemann JD, Getts MT, Miller SD: Antiviral immune responses: triggers of or triggered by autoimmunity? Nat Rev Immunol 2009, 9:246-258.
• [24]Li J, Ramenaden ER, Peng J, Koito H, Volpe JJ, Rosenberg PA: Tumor necrosis factor alpha mediates lipopolysaccharide-induced microglial toxicity to developing oligodendrocytes when astrocytes are present. J Neurosci 2008, 28:5321-5330.
• [25]Kim S, Steelman AJ, Koito H, Li J: Astrocytes promote TNF-mediated toxicity to oligodendrocyte precursors. J Neurochem 2011, 116:53-66.
• [26]Town T, Jeng D, Alexopoulou L, Tan J, Flavell RA: Microglia recognize double-stranded RNA via TLR3. J Immunol 2006, 176:3804-3812.
• [27]Carpentier PA, Begolka WS, Olson JK, Elhofy A, Karpus WJ, Miller SD: Differential activation of astrocytes by innate and adaptive immune stimuli. Glia 2005, 49:360-374.
• [28]Li J, Baud O, Vartanian T, Volpe JJ, Rosenberg PA: Peroxynitrite generated by inducible nitric oxide synthase and NADPH oxidase mediates microglial toxicity to oligodendrocytes. Proc Natl Acad Sci USA 2005, 102:9936-9941.
• [29]Steelman AJ, Dean DD, Young CR, Smith R, Prentice TW, Meagher MW, Welsh CJ: Restraint stress modulates virus specific adaptive immunity during acute Theiler's virus infection. Brain Behav Immun 2009, 17:109-119.
• [30]Kim S, Steelman AJ, Zhang Y, Kinney HC, Li J: Aberrant Upregulation of Astroglial Ceramide Potentiates Oligodendrocyte Injury. Brain Pathol 2011, in press.
• [31]Olson JK, Ludovic Croxford J, Miller SD: Innate and adaptive immune requirements for induction of autoimmune demyelinating disease by molecular mimicry. Mol Immunol 2004, 40:1103-1108.
• [32]Carpentier PA, Williams BR, Miller SD: Distinct roles of protein kinase R and toll-like receptor 3 in the activation of astrocytes by viral stimuli. Glia 2007, 55:239-252.
• [33]Kim H, Yang E, Lee J, Kim SH, Shin JS, Park JY, Choi SJ, Kim SJ, Choi IH: Double-stranded RNA mediates interferon regulatory factor 3 activation and interleukin-6 production by engaging Toll-like receptor 3 in human brain astrocytes. Immunology 2008, 124:480-488.
• [34]Scumpia PO, Kelly KM, Reeves WH, Stevens BR: Double-stranded RNA signals antiviral and inflammatory programs and dysfunctional glutamate transport in TLR3-expressing astrocytes. Glia 2005, 52:153-162.
• [35]Yoshida H, Imaizumi T, Lee SJ, Tanji K, Sakaki H, Matsumiya T, Ishikawa A, Taima K, Yuzawa E, Mori F, et al.: Retinoic acid-inducible gene-I mediates RANTES/CCL5 expression in U373MG human astrocytoma cells stimulated with double-stranded RNA. Neurosci Res 2007, 58:199-206.
• [36]Arnett HA, Mason J, Marino M, Suzuki K, Matsushima GK, Ting JP: TNF alpha promotes proliferation of oligodendrocyte progenitors and remyelination. Nat Neurosci 2001, 4:1116-1122.
• [37]Hofman FM, Hinton DR, Johnson K, Merrill JE: Tumor necrosis factor identified in multiple sclerosis brain. J Exp Med 1989, 170:607-612.
• [38]Sun N, Grzybicki D, Castro RF, Murphy S, Perlman S: Activation of astrocytes in the spinal cord of mice chronically infected with a neurotropic coronavirus. Virology 1995, 213:482-493.
• [39]Selmaj K, Raine CS, Cannella B, Brosnan CF: Identification of lymphotoxin and tumor necrosis factor in multiple sclerosis lesions. J Clin Invest 1991, 87:949-954.
• [40]Zhou S, Halle A, Kurt-Jones EA, Cerny AM, Porpiglia E, Rogers M, Golenbock DT, Finberg RW: Lymphocytic choriomeningitis virus (LCMV) infection of CNS glial cells results in TLR2-MyD88/Mal-dependent inflammatory responses. J Neuroimmunol 2008, 194:70-82.
• [41]Pang Y, Campbell L, Zheng B, Fan L, Cai Z, Rhodes P: Lipopolysaccharide-activated microglia induce death of oligodendrocyte progenitor cells and impede their development. Neuroscience 2010, 166:464-475.
• [42]Akassoglou K, Probert L, Kontogeorgos G, Kollias G: Astrocyte-specific but not neuron-specific transmembrane TNF triggers inflammation and degeneration in the central nervous system of transgenic mice. J Immunol 1997, 158:438-445.
• [43]Zajicek JP, Wing M, Scolding NJ, Compston DA: Interactions between oligodendrocytes and microglia. A major role for complement and tumour necrosis factor in oligodendrocyte adherence and killing. Brain 1992, 115(Pt 6):1611-1631.
• [44]Selmaj KW, Raine CS: Tumor necrosis factor mediates myelin and oligodendrocyte damage in vitro. Ann Neurol 1988, 23:339-346.
• [45]Hoek RM, Ruuls SR, Murphy CA, Wright GJ, Goddard R, Zurawski SM, Blom B, Homola ME, Streit WJ, Brown MH, et al.: Down-regulation of the macrophage lineage through interaction with OX2 (CD200). Science 2000, 290:1768-1771.
• [46]Zujovic V, Benavides J, Vige X, Carter C, Taupin V: Fractalkine modulates TNF-alpha secretion and neurotoxicity induced by microglial activation. Glia 2000, 29:305-315.
• [47]Setzu A, Lathia JD, Zhao C, Wells K, Rao MS, Ffrench-Constant C, Franklin RJ: Inflammation stimulates myelination by transplanted oligodendrocyte precursor cells. Glia 2006, 54:297-303.
• [48]Glezer I, Lapointe A, Rivest S: Innate immunity triggers oligodendrocyte progenitor reactivity and confines damages to brain injuries. FASEB J 2006, 20:750-752.
• [49]Jenkins HG, Ikeda H: Tumour necrosis factor causes an increase in axonal transport of protein and demyelination in the mouse optic nerve. J Neurol Sci 1992, 108:99-104.
• [50]Simmons RD, Willenborg DO: Direct injection of cytokines into the spinal cord causes autoimmune encephalomyelitis-like inflammation. J Neurol Sci 1990, 100:37-42.
• [51]Rodriguez M, Zoecklein L, Papke L, Gamez J, Denic A, Macura S, Howe C: Tumor Necrosis Factor alpha is Reparative via TNFR1 in the Hippocampus and via TNFR2 in the Striatum after Virus-Induced Encephalitis. Brain Pathol 2008, 19:12-26.
• [52]Kirkman NJ, Libbey JE, Wilcox KS, White HS, Fujinami RS: Innate but not adaptive immune responses contribute to behavioral seizures following viral infection. Epilepsia 2010, 51:454-464.
• [53]Mycko MP, Papoian R, Boschert U, Raine CS, Selmaj KW: cDNA microarray analysis in multiple sclerosis lesions: detection of genes associated with disease activity. Brain 2003, 126:1048-1057.
• [54]Raine CS, Bonetti B, Cannella B: Multiple sclerosis: expression of molecules of the tumor necrosis factor ligand and receptor families in relationship to the demyelinated plaque. Rev Neurol (Paris) 1998, 154:577-585.
• [55]Group TLMSSGaTUoBCMMA: TNF neutralization in MS: results of a randomized, placebo-controlled multicenter study. Neurology 1999, 53:457-465.
• [56]van Oosten BW, Barkhof F, Truyen L, Boringa JB, Bertelsmann FW, von Blomberg BM, Woody JN, Hartung HP, Polman CH: Increased MRI activity and immune activation in two multiple sclerosis patients treated with the monoclonal anti-tumor necrosis factor antibody cA2. Neurology 1996, 47:1531-1534.
• [57]Fromont A, De Seze J, Fleury MC, Maillefert JF, Moreau T: Inflammatory demyelinating events following treatment with anti-tumor necrosis factor. Cytokine 2009, 45:55-57.
• [58]Mohan N, Edwards ET, Cupps TR, Oliverio PJ, Sandberg G, Crayton H, Richert JR, Siegel JN: Demyelination occurring during anti-tumor necrosis factor alpha therapy for inflammatory arthritides. Arthritis Rheum 2001, 44:2862-2869.
• [59]Tauber T, Daniel D, Barash J, Turetz J, Morad Y: Optic neuritis associated with etanercept therapy in two patients with extended oligoarticular juvenile idiopathic arthritis. Rheumatology (Oxford) 2005, 44:405.
• [60]Tauber T, Turetz J, Barash J, Avni I, Morad Y: Optic neuritis associated with etanercept therapy for juvenile arthritis. J AAPOS 2006, 10:26-29.
• [61]Sicotte NL, Voskuhl RR: Onset of multiple sclerosis associated with anti-TNF therapy. Neurology 2001, 57:1885-1888.
• [62]De Jager PL, Jia X, Wang J, de Bakker PI, Ottoboni L, Aggarwal NT, Piccio L, Raychaudhuri S, Tran D, Aubin C, et al.: Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nat Genet 2009, 41:776-782.
• [63]Swaminathan B, Matesanz F, Cavanillas ML, Alloza I, Otaegui D, Olascoaga J, Cenit MC, de las Heras V, Barcina MG, Arroyo R, et al.: Validation of the CD6 and TNFRSF1A loci as risk factors for multiple sclerosis in Spain. J Neuroimmunol 2010, 223:100-103.