Astrocyte response to IFN-γ limits IL-6-mediated microglia activation and progressive autoimmune encephalomyelitis

• Type of Material: Article
• Authors: Carine Savarin, Cleveland Clinic Foundation; David R. Hinton, University of Southern California, Los Angeles; Alice Valentin-Torres, Cleveland Clinic Foundation; Zhihong Chen, Emory University; Bruce D. Trapp, Cleveland Clinic Foundation; Cornelia C. Bergmann, Cleveland Clinic Foundation; Stephen A. Stohlman, Cleveland Clinic Foundation
• Language: English
• Date: 2015-12-12
• Publisher: BMC (part of Springer Nature)
• Publication Version: Final Published Version
• Copyright Statement: © Savarin et al.; licensee BioMed Central. 2015
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1186/s12974-015-0293-9
• Title of Journal or Parent Work: Journal of Neuroinflammation
• ISSN: 1742-2094
• Volume: 12
• Issue: 1
• Start Page: 79
• End Page: 79
• Grant/Funding Information: This work was supported by the Multiple Sclerosis Society research grant RG4007B5 and Cancer Center Support grant P30CA014089.
• Keywords: Macrophage Activation; Promoter Regions, Genetic; Interferon-gamma; Microglia; Mice; Encephalomyelitis, Autoimmune, Experimental; Mice, Inbred C57BL; Animals; Astrocytes; Demyelinating Diseases; Multiple Sclerosis; Antibodies, Neutralizing; Mice, Transgenic; Humans; Interleukin-6; Gliosis; Glial Fibrillary Acidic Protein
• Research Categories: Health Sciences, Pathology; Health Sciences, Immunology

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.