title: Astrocyte response to IFN-γ limits IL-6-mediated microglia activation and progressive autoimmune encephalomyelitis.
abstract: BACKGROUND
  Therapeutic modalities effective in patients with progressive forms of multiple sclerosis (MS) are limited. In a murine model of progressive MS, the sustained disability during the chronic phase of experimental autoimmune encephalomyelitis (EAE) correlated with elevated expression of interleukin (IL)-6, a cytokine with pleiotropic functions and therapeutic target for non-central nervous system (CNS) autoimmune disease. Sustained IL-6 expression in astrocytes restricted to areas of demyelination suggested that IL-6 plays a major role in disease progression during chronic EAE.
  
  
  METHODS
  A progressive form of EAE was induced using transgenic mice expressing a dominant negative interferon-γ (IFN-γ) receptor alpha chain under control of human glial fibrillary acidic protein (GFAP) promoter (GFAPγR1Δ mice). The role of IL-6 in regulating progressive CNS autoimmunity was assessed by treating GFAPγR1Δ mice with anti-IL-6 neutralizing antibody during chronic EAE.
  
  
  RESULTS
  IL-6 neutralization restricted disease progression and decreased disability, myelin loss, and axonal damage without affecting astrogliosis. IL-6 blockade reduced CNS inflammation by limiting inflammatory cell proliferation; however, the relative frequencies of CNS leukocyte infiltrates, including the Th1, Th17, and Treg CD4 T cell subsets, were not altered. IL-6 blockade rather limited the activation and proliferation of microglia, which correlated with higher expression of Galectin-1, a regulator of microglia activation expressed by astrocytes.
  
  
  CONCLUSIONS
  These data demonstrate that astrocyte-derived IL-6 is a key mediator of progressive disease and support IL-6 blockade as a viable intervention strategy to combat progressive MS.
authors.affiliation: Department of Neurosciences NC-30, Lerner Research Institute, The Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA. savaric@ccf.org.
authors.forename: Carine
authors.initials: C
authors.lastname: Savarin
authors.affiliation: Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA. dhinton@usc.edu.
authors.forename: David R
authors.initials: DR
authors.lastname: Hinton
authors.affiliation: Department of Neurosciences NC-30, Lerner Research Institute, The Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA. valenta@ccf.org.
authors.forename: Alice
authors.initials: A
authors.lastname: Valentin-Torres
authors.affiliation: Department of Neurosciences NC-30, Lerner Research Institute, The Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA. chenz2@ccf.org.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Neurosciences NC-30, Lerner Research Institute, The Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA. trappb@ccf.org.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Trapp
authors.affiliation: Department of Neurosciences NC-30, Lerner Research Institute, The Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA. bergmac@ccf.org.
authors.forename: Cornelia C
authors.initials: CC
authors.lastname: Bergmann
authors.affiliation: Department of Neurosciences NC-30, Lerner Research Institute, The Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, 44195, USA. stohlms2@ccf.org.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Stohlman
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000627:therapeutic use; D001253:Astrocytes / Q000187:drug effects*; D003711:Demyelinating Diseases / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology*; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D005911:Gliosis / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D015850:Interleukin-6 / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects*; D009103:Multiple Sclerosis / Q000188:drug therapy; D011401:Promoter Regions, Genetic / Q000235:genetics; D000093242:Interleukin-6 Inhibitors
chemical_list: D057134:Antibodies, Neutralizing; D005904:Glial Fibrillary Acidic Protein; D007371:Interferon-gamma; D015850:Interleukin-6; D000093242:Interleukin-6 Inhibitors