Title |
Astrocyte response to IFN-γ limits IL-6-mediated microglia activation and progressive autoimmune encephalomyelitis
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Published in |
Journal of Neuroinflammation, April 2015
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DOI | 10.1186/s12974-015-0293-9 |
Pubmed ID | |
Authors |
Carine Savarin, David R Hinton, Alice Valentin-Torres, Zhihong Chen, Bruce D Trapp, Cornelia C Bergmann, Stephen A Stohlman |
Abstract |
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. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Chile | 1 | 1% |
Unknown | 74 | 99% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 17 | 23% |
Researcher | 11 | 15% |
Student > Doctoral Student | 7 | 9% |
Student > Master | 6 | 8% |
Student > Bachelor | 5 | 7% |
Other | 16 | 21% |
Unknown | 13 | 17% |
Readers by discipline | Count | As % |
---|---|---|
Neuroscience | 16 | 21% |
Medicine and Dentistry | 11 | 15% |
Agricultural and Biological Sciences | 9 | 12% |
Biochemistry, Genetics and Molecular Biology | 6 | 8% |
Immunology and Microbiology | 6 | 8% |
Other | 9 | 12% |
Unknown | 18 | 24% |