Journal of Neuroinflammation | |
IFN-gamma signaling in the central nervous system controls the course of experimental autoimmune encephalomyelitis independently of the localization and composition of inflammatory foci | |
Athena M Soulika3  David Pleasure2  Sarah Chanamara1  Eunyoung Lee3  | |
[1] Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children Northern California, Sacramento, California, USA, 95817;The Department of Neurology, School of Medicine, University of California Davis, Sacramento, California, USA, 95817;Department of Dermatology, School of Medicine, University of California, Davis Sacramento, California, USA, 95816 | |
关键词: inflammation; STAT1; IFNγ; EAE; brainstem; cerebellum; microglia; | |
Others : 1212882 DOI : 10.1186/1742-2094-9-7 |
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received in 2011-07-16, accepted in 2012-01-16, 发布年份 2012 |
【 摘 要 】
Background
Murine experimental autoimmune encephalomyelitis (EAE), a model for multiple sclerosis, presents typically as ascending paralysis. However, in mice in which interferon-gamma (IFNγ) signaling is disrupted by genetic deletion, limb paralysis is accompanied by atypical deficits, including head tilt, postural imbalance, and circling, consistent with cerebellar/vestibular dysfunction. This was previously attributed to intense cerebellar and brainstem infiltration by peripheral immune cells and formation of neutrophil-rich foci within the CNS. However, the exact mechanism by which IFNγ signaling prohibits the development of vestibular deficits, and whether the distribution and composition of inflammatory foci within the CNS affects the course of atypical EAE remains elusive.
Methods
We induced EAE in IFNγ-/- mice and bone marrow chimeric mice in which IFNγR is not expressed in the CNS but is intact in the periphery (IFNγRCNSKO) and vice versa (IFNγRperiKO). Blood-brain barrier permeability was determined by Evans blue intravenous administration at disease onset. Populations of immune cell subsets in the periphery and the CNS were quantified by flow cytometry. CNS tissues isolated at various time points after EAE induction, were analyzed by immunohistochemistry for composition of inflammatory foci and patterns of axonal degeneration.
Results
Incidence and severity of atypical EAE were more pronounced in IFNγRCNSKO as compared to IFNγRperiKO mice. Contrary to what we anticipated, cerebella/brainstems of IFNγRCNSKO mice were only minimally infiltrated, while the same areas of IFNγRperiKO mice were extensively populated by peripheral immune cells. Furthermore, the CNS of IFNγRperiKO mice was characterized by persistent neutrophil-rich foci as compared to IFNγRCNSKO. Immunohistochemical analysis of the CNS of IFNγ-/- and IFNγR chimeric mice revealed that IFNγ protective actions are exerted through microglial STAT1.
Conclusions
Alterations in distribution and composition of CNS inflammatory foci are not sufficient for the onset of atypical EAE. IFNγ dictates the course of neuroinflammatory disorders mainly through actions exerted within the CNS. This study provides strong evidence that link microglial STAT1 inactivation to vestibular dysfunction.
【 授权许可】
2012 Lee et al; licensee BioMed Central Ltd.
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【 参考文献 】
- [1]Soulika AM, Lee E, McCauley E, Miers L, Bannerman P, Pleasure D: Initiation and Progression of Axonopathy in Experimental Autoimmune Encephalomyelitis. Journal of Neuroscience 2009, 29:14965-14979.
- [2]Trapp BD, Stys PK: Virtual hypoxia and chronic necrosis of demyelinated axons in multiple sclerosis. Lancet Neurol 2009, 8:280-291.
- [3]Langdon DW, Thompson AJ: Multiple sclerosis: a preliminary study of selected variables affecting rehabilitation outcome. Multiple Sclerosis 1999, 5:94-100.
- [4]Naismith RT, Trinkaus K, Cross AH: Phenotype and prognosis in African-Americans with multiple sclerosis: a retrospective chart review. Multiple Sclerosis 2006, 12:775-781.
- [5]Zaaraoui W, Reuter F, Rico A, Faivre A, Crespy L, Malikova I, Soulier E, Viout P, Le Fur Y, Confort-Gouny S, et al.: Occurrence of neuronal dysfunction during the first 5 years of multiple sclerosis is associated with cognitive deterioration. Journal of Neurology 2010.
- [6]Boehm U, Klamp T, Groot M, Howard JC: Cellular responses to interferon-gamma. Annual Review of Immunology 1997, 15:749-795.
- [7]Farrar MA, Schreiber RD: The Molecular Cell Biology of Interferon-Gamma and Its Receptor. Annual Review of Immunology 1993, 11:571-611.
- [8]Neumann H, Schmidt H, Wilharm E, Behrens L, Wekerle H: Interferon gamma gene expression in sensory neurons: Evidence for autocrine gene regulation. Journal of Experimental Medicine 1997, 186:2023-2031.
- [9]Sun L, Tian ZZ, Wang JP: A direct cross-talk between interferon-gamma and sonic hedgehog signaling that leads to the proliferation of neuronal precursor cells. Brain Behavior and Immunity 2010, 24:220-228.
- [10]Kelchtermans H, Billiau A, Matthys P: How interferon-gamma keeps autoimmune diseases in check. Trends Immunol 2008, 29:479-486.
- [11]Muhl H, Pfeilschifter J: Anti-inflammatory properties of pro-inflammatory interferon-gamma. Int Immunopharmacol 2003, 3:1247-1255.
- [12]Chu CQ, Wittmer S, Dalton DK: Failure to suppress the expansion of the activated CD4 T cell population in interferon gamma-deficient mice leads to exacerbation of experimental autoimmune encephalomyelitis. Journal of Experimental Medicine 2000, 192:123-128.
- [13]Dalton DK, Haynes L, Chu CQ, Swain SL, Wittmer S: Interferon gamma eliminates responding CD4 T cells during mycobacterial infection by inducing apoptosis of activated CD4 T cells. Journal of Experimental Medicine 2000, 192:117-122.
- [14]Wang ZJ, Hong J, Sun W, Xu GW, Li NL, Chen X, Liu A, Xu LY, Sun B, Zhang JWZ: Role of IFN-gamma in induction of Foxp3 and conversion of CD4(+)CD25(-) T cells to CD4(+) Tregs. Journal of Clinical Investigation 2006, 116:2434-2441.
- [15]Hashioka S, Klegeris A, Schwab C, McGeer PL: Interferon-gamma-dependent cytotoxic activation of human astrocytes and astrocytoma cells. Neurobiology of Aging 2009, 30:1924-1935.
- [16]Popko B, Corbin JG, Baerwald KD, Dupree J, Garcia AM: The effects of interferon-gamma on the central nervous system. Molecular Neurobiology 1997, 14:19-35.
- [17]Rubio N, Defelipe C: Demonstration of the Presence of a Specific Interferon-Gamma Receptor on Murine Astrocyte Cell-Surface. Journal of Neuroimmunology 1991, 35:111-117.
- [18]Torres C, Aranguez I, Rubio N: Expression of Interferon-Gamma Receptors on Murine Oligodendrocytes and Its Regulation by Cytokines and Mitogens. Immunology 1995, 86:250-255.
- [19]Tsuda M, Masuda T, Kitano J, Shimoyama H, Tozaki-Saitoh H, Inoue K: IFN-gamma receptor signaling mediates spinal microglia activation driving neuropathic pain. Proceedings of the National Academy of Sciences of the United States of America 2009, 106:8032-8037.
- [20]Vikman K, Robertson B, Grant G, Liljeborg A, Kristensson K: Interferon-gamma receptors are expressed at synapses in the rat superficial dorsal horn and lateral spinal nucleus. Journal of Neurocytology 1998, 27:749-759.
- [21]Billiau A, Heremans H, Vandekerckhove F, Dijkmans R, Sobis H, Meulepas E, Carton H: Enhancement of Experimental Allergic Encephalomyelitis in Mice by Antibodies against Ifn-Gamma. Journal of Immunology 1988, 140:1506-1510.
- [22]Furlan R, Brambilla E, Ruffini F, Poliani PL, Bergami A, Marconi PC, Franciotta DM, Penna G, Comi G, Adorini L, Martino G: Intrathecal delivery of IFN-gamma protects C57BL/6 mice from chronic-progressive experimental autoimmune encephalomyelitis by increasing apoptosis of central nervous system-infiltrating lymphocytes. Journal of Immunology 2001, 167:1821-1829.
- [23]Voorthuis JA, Uitdehaag BM, De Groot CJ, Goede PH, van der Meide PH, Dijkstra CD: Suppression of experimental allergic encephalomyelitis by intraventricular administration of interferon-gamma in Lewis rats. Clin Exp Immunol 1990, 81:183-188.
- [24]Lees JR, Golumbek PT, Sim J, Dorsey D, Russell JH: Regional CNS responses to IFN-gamma determine lesion localization patterns during EAE pathogenesis. Journal of Experimental Medicine 2008, 205:2633-2642.
- [25]Willenborg DO, Fordham SA, Staykova MA, Ramshaw IA, Cowden WB: IFN-gamma is critical to the control of murine autoimmune encephalomyelitis and regulates both in the periphery and in the target tissue: A possible role for nitric oxide. Journal of Immunology 1999, 163:5278-5286.
- [26]Lees JR, Iwakura Y, Russell JH: Host T cells are the main producers of IL-17 within the central nervous system during initiation of experimental autoimmune encephalomyelitis of Th1 cell lines. Journal of Immunology 2008, 180:8066-8072.
- [27]Skundric DS, Kim C, Tse HY, Raine CS: Homing of T cells to the central nervous system throughout the course of relapsing experimental autoimmune encephalomyelitis in Thy-1 congenic mice. Journal of Neuroimmunology 1993, 46:113-121.
- [28]Kuerten S, Kostova-Bales DA, Frenzel LP, Tigno JT, Tary-Lehmann M, Angelov DN, Lehmann PV: MP4- and MOG:35-55-induced EAE in C57BL/6 mice differentially targets brain, spinal cord and cerebellum. Journal of Neuroimmunology 2007, 189:31-40.
- [29]Tonra JR: Cerebellar susceptibility to experimental autoimmune encephalomyelitis in SJL/J mice: potential interaction of immunology with vascular anatomy. Cerebellum 2002, 1:57-68.
- [30]Zheng JZ, Bizzozero OA: Accumulation of Protein Carbonyls Within Cerebellar Astrocytes in Murine Experimental Autoimmune Encephalomyelitis. Journal of Neuroscience Research 2010, 88:3376-3385.
- [31]Bannerman P, Hahn A, Soulika A, Gallo V, Pleasure D: Astrogliosis in EAE spinal cord: Derivation from radial glia, and relationships to oligodendroglia. Glia 2007, 55:57-64.
- [32]Abromson-Leeman S, Bronson R, Luo Y, Berman M, Leeman R, Leeman J, Dorf M: T-cell properties determine disease site, clinical presentation, and cellular pathology of experimental autoimmune encephalomyelitis. American Journal of Pathology 2004, 165:1519-1533.
- [33]Tran EH, Prince EN, Owens T: IFN-gamma shapes immune invasion of the central nervous system via regulation of chemokines. Journal of Immunology 2000, 164:2759-2768.
- [34]Siffrin V, Radbruch H, Glumm R, Niesner R, Paterka M, Herz J, Leuenberger T, Lehmann SM, Luenstedt S, Rinnenthal JL, et al.: In vivo imaging of partially reversible th17 cell-induced neuronal dysfunction in the course of encephalomyelitis. Immunity 2010, 33:424-436.
- [35]Pollinger B, Krishnamoorthy G, Berer K, Lassmann H, Bosl MR, Dunn R, Domingues HS, Holz A, Kurschus FC, Wekerle H: Spontaneous relapsing-remitting EAE in the SJL/J mouse: MOG-reactive transgenic T cells recruit endogenous MOG-specific B cells. Journal of Experimental Medicine 2009, 206:1303-1316.
- [36]De la Hera A, Alvarez-Mon M, Sanchez-Madrid F, Martinez C, Durantez A: Co-expression of Mac-1 and p150,95 on CD5+ B cells. Structural and functional characterization in a human chronic lymphocytic leukemia. European Journal of Immunology 1988, 18:1131-1134.
- [37]McFarland HI, Nahill SR, Maciaszek JW, Welsh RM: CD11b (Mac-1): a marker for CD8+ cytotoxic T cell activation and memory in virus infection. Journal of Immunology 1992, 149:1326-1333.
- [38]Springer T, Galfre G, Secher DS, Milstein C: Mac-1: a macrophage differentiation antigen identified by monoclonal antibody. European Journal of Immunology 1979, 9:301-306.
- [39]Wright SD, Rao PE, Van Voorhis WC, Craigmyle LS, Iida K, Talle MA, Westberg EF, Goldstein G, Silverstein SC: Identification of the C3bi receptor of human monocytes and macrophages by using monoclonal antibodies. Proc Natl Acad Sci USA 1983, 80:5699-5703.
- [40]Zarling JM, Kung PC: Monoclonal antibodies which distinguish between human NK cells and cytotoxic T lymphocytes. Nature 1980, 288:394-396.
- [41]Bjartmar C, Trapp BD: Axonal degeneration and progressive neurologic disability in multiple sclerosis. Neurotox Res 2003, 5:157-164.
- [42]Bjartmar C, Wujek JR, Trapp BD: Axonal loss in the pathology of MS: consequences for understanding the progressive phase of the disease. J Neurol Sci 2003, 206:165-171.
- [43]Carpenter MB, Alling FA, Bard DS: Lesions of the Descending Vestibular Nucleus in the Cat. Journal of Comparative Neurology 1960, 114:39.
- [44]Shriver LP, Dittel BN: T-cell-mediated disruption of the neuronal microtubule network: correlation with early reversible axonal dysfunction in acute experimental autoimmune encephalomyelitis. American Journal of Pathology 2006, 169:999-1011.
- [45]Abromson-Leeman S, Ladell DS, Bronson RT, Dorf ME: Heterogeneity of EAE mediated by multiple distinct T-effector subsets. Journal of Neuroimmunology 2007, 192:3-12.
- [46]Bettelli E, Sullivan B, Szabo SJ, Sobel RA, Glimcher LH, Kuchroo VK: Loss of T-bet, but not STAT1, prevents the development of experimental autoimmune encephalomyelitis. Journal of Experimental Medicine 2004, 200:79-87.
- [47]Stromnes IM, Cerretti LM, Liggitt D, Harris RA, Goverman JM: Differential regulation of central nervous system autoimmunity by T(H)1 and T(H)17 cells. Nature Medicine 2008, 14:337-342.
- [48]Olson JK, Girvin AM, Miller SD: Direct activation of innate and antigen-presenting functions of microglia following infection with Theiler's virus. J Virol 2001, 75:9780-9789.
- [49]Neumann J, Sauerzweig S, Roenicke 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. Journal of Neuroscience 2008, 28:5965-5975.
- [50]Streit WJ: Microglia as neuroprotective, immunocompetent cells of the CNS. Glia 2002, 40:133-139.
- [51]Walton NM, Sutter BM, Laywell ED, Levkoff LH, Kearns SM, Marshall GP, Scheffler B, Steindler DA: Microglia instruct subventricular zone neurogenesis. Glia 2006, 54:815-825.
- [52]Ziv Y, Ron N, Butovsky O, Landa G, Sudai E, Greenberg N, Cohen H, Kipnis J, Schwartz M: Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood. Nature Neuroscience 2006, 9:268-275.
- [53]Iliev AI, Stringaris AK, Nau R, Neumann H: Neuronal injury mediated via stimulation of microglial toll-like receptor-9 (TLR9). Faseb Journal 2004, 18:412-414.
- [54]Kaushal V, Schlichter LC: Mechanisms of microglia-mediated neurotoxicity in a new model of the stroke penumbra. Journal of Neuroscience 2008, 28:2221-2230.
- [55]Liu B, Gao HM, Wang JY, Jeohn GH, Cooper CL, Hong JS: Role of nitric oxide in inflammation-mediated neurodegeneration. Nitric Oxide: Novel Actions, Deleterious Effects and Clinical Potential 2002, 962:318-331.
- [56]Nikic I, Merkler D, Sorbara C, Brinkoetter M, Kreutzfeldt M, Bareyre FM, Bruck W, Bishop D, Misgeld T, Kerschensteiner M: A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis. Nature Medicine 2011, 17:495-U135.
- [57]Waxman SG: Axonal conduction and injury in multiple sclerosis: the role of sodium channels. Nature Reviews Neuroscience 2006, 7:932-941.
- [58]Maskey D, Pradhan J, Kim HJ, Park KS, Ahn SC, Kim MJ: Immunohistochemical localization of calbindin D28-k, parvalbumin, and calretinin in the cerebellar cortex of the circling mouse. Neuroscience Letters 2010, 483:132-136.