Abstract
BackgroundTherapeutic 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.MethodsA 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.ResultsIL-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.ConclusionsThese 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.
Highlights
Therapeutic modalities effective in patients with progressive forms of multiple sclerosis (MS) are limited
Astrocytes secrete IL-6 during progressive EAE Astrocytes are the predominant source of IL-6 in the central nervous system (CNS) of patients with MS and mice with acute EAE [27], and during acute EAE, its expression is independent of the ability of astrocytes to respond to IFN-γ [9]
These data demonstrate that the predominant source of IL-6 during acute EAE is not altered by the inability of astrocytes to respond to IFN-γ
Summary
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. Multiple sclerosis (MS) is characterized by focal inflammation within the central nervous system (CNS), demyelination, axonal damage, and neurological disability [1]. Experimental autoimmune encephalomyelitis (EAE), a rodent model with numerous characteristics in common with MS, has been essential in understanding the mechanisms underlying MS pathogenesis and has Savarin et al Journal of Neuroinflammation (2015) 12:79 model of progressive MS using GFAPγR1Δ transgenic mice in which astrocytes are deficient in IFN-γ signaling characterized by prolonged disability and increased mortality [9]. The progressive disability and sustained demyelination correlated with elevated expression of IL-6, a cytokine with pleiotropic functions and a therapeutic target for non-CNS autoimmune diseases, such as rheumatoid arthritis [10]. Inhibition of IL-6 signaling is effective in several murine models of inflammatory diseases, including colitis, asthma, and cancer [11,12,13]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
