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

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. © 2015 savarin et al.; licensee biomed central.