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

• Published in: Journal of neuroinflammation Vol. 12; no. 1; p. 79
• Main Authors: Savarin, Carine, Hinton, David R, Valentin-Torres, Alice, Chen, Zhihong, Trapp, Bruce D, Bergmann, Cornelia C, Stohlman, Stephen A
• Format: Journal Article
• Language: English
• Published: England BioMed Central 22.04.2015
• Subjects: Animals; Antibodies, Neutralizing - therapeutic use; Astrocytes - drug effects; Demyelinating Diseases - pathology; Encephalomyelitis, Autoimmune, Experimental - drug therapy; Encephalomyelitis, Autoimmune, Experimental - immunology; Glial Fibrillary Acidic Protein - genetics; Gliosis - immunology; Humans; Interferon-gamma - pharmacology; Interleukin-6 - antagonists & inhibitors; Interleukin-6 - pharmacology; Macrophage Activation - drug effects; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia - drug effects; Multiple Sclerosis - drug therapy; Promoter Regions, Genetic - genetics
• ISSN: 1742-2094; 1742-2094
• DOI: 10.1186/s12974-015-0293-9

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. 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. 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. 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.