title: IFN-gamma signaling in the central nervous system controls the course of experimental autoimmune encephalomyelitis independently of the localization and composition of inflammatory foci.
abstract: 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.
authors.affiliation: Institute for Pediatric Regenerative Medicine, Shriners Hospitals for Children Northern California, Sacramento, California 95817, USA.
authors.forename: Eunyoung
authors.initials: E
authors.lastname: Lee
authors.forename: Sarah
authors.initials: S
authors.lastname: Chanamara
authors.forename: David
authors.initials: D
authors.lastname: Pleasure
authors.forename: Athena M
authors.initials: AM
authors.lastname: Soulika
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001812:Blood-Brain Barrier / Q000503:physiopathology; D002490:Central Nervous System / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000150:complications / Q000276:immunology / Q000473:pathology*; D005434:Flow Cytometry; D006023:Glycoproteins / Q000009:adverse effects; D007371:Interferon-gamma / Q000172:deficiency; D017493:Leukocyte Common Antigens / Q000235:genetics; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology; D008198:Lymph Nodes / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein; D009422:Nervous System Diseases / Q000209:etiology; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000276:immunology; D010446:Peptide Fragments / Q000009:adverse effects; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D013154:Spleen / Q000473:pathology
chemical_list: D015703:Antigens, CD; D016207:Cytokines; D006023:Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; C445081:myelin oligodendrocyte glycoprotein (35-55); D007371:Interferon-gamma; D017493:Leukocyte Common Antigens; C516770:Ptprc protein, mouse