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

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.

Sphingosine 1-phosphate receptor modulation suppresses pathogenic astrocyte activation and chronic progressive CNS inflammation

“…The CNS innate immune response plays a central role in the progressive phase of NOD EAE (1,3,5,6,(35)(36)(37)(38)(39). Thus, we analyzed the transcriptional profile of astrocytes, microglia, and proinflammatory monocytes isolated from vehicle-and FTY720-treated mice 120 d after EAE induction using custom-made Nanostring nCounter arrays (Table S1) (2).…”

“…Recent findings, however, suggest that the innate immune response in the CNS promotes disease progression in MS. Indeed, astrocytes (the most abundant cell population in the mammalian CNS), microglia, and proinflammatory monocytes are thought to promote neurodegeneration, demyelination, and scar formation (1)(2)(3)(4)(5)(6). However, therapeutic strategies targeting these cell types remain elusive to date.…”

“…Sphingosine 1-phosphate (S1P) is a sphingosine-containing lipid generated from ceramide, which binds G protein-coupled receptors [Sphingosine 1-phospate receptors (S1PRs) [1][2][3][4][5] and modulates the proliferation and trafficking of several cell types, including immune cells. Consequently, S1PRs are considered candidate therapeutic targets for inflammatory diseases, including MS, psoriasis, asthma, and polyneuritis, and also for hematologic and solid tumors, ischemic stroke, and wound healing (7)(8)(9)(10)(11)(12).…”

TNFR2 limits proinflammatory astrocyte functions during EAE induced by pathogenic DR2b-restricted T cells

“…Reactive astrocytes express increased levels of IL-6, GM-CSF, OPN, and TNF during the chronic stage of EAE, resulting in astrogliosis, neuronal damage, and axonal pathology (39,62,63). Furthermore, astrocyte IL-6 facilitates CNS entry of T cells by increasing BBB permeability and increased adhesion molecule expression by endothelial cells (64), and it activates microglial cells to become proinflammatory and promote damage to oligodendrocytes and axons (64,65). Our data indicate that TNFR2 regulates or suppresses the expression of IL-6, whereas TNFR1 may be important for its induction.…”

Regional astrocyte interferon-γ signaling regulates immunoproteasome-mediated protection during chronic autoimmunity

“…Using a signaling deficient dominant-negative Ifngr1 driven by the Gfap promotor, the protective effects of IFNγ signaling during chronic EAE was linked to astrocytes (57). While follow-up studies indicate these effects may be due to altered cytokine release influencing microglia (58), the astrocyte-specific mechanisms of IFNγ-mediated protection are not defined.…”