Control of autoimmune CNS inflammation by astrocytes

Rothhammer, Veit; Quintana, Francisco J.

doi:10.1007/s00281-015-0515-3

Cited by 157 publications

(122 citation statements)

References 137 publications

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“…This is in agreement with recently published reports suggesting that DMF, not MMF, is anti‐inflammatory in human myeloid cells 9, 13, 14. In response to inflammation, astrocytes secrete chemokines to recruit immune cells, a process further facilitated by their position at the interface of the blood–brain barrier 18. Here, we demonstrated for the first time in astrocytes that CCL2 and CXCL10, two chemokines secreted by astrocytes that influence MS pathology and oligodendrocyte differentiation,31, 32 are reduced in the presence of DMF.…”

Section: Discussionmentioning

confidence: 66%

“…Astrocytes also contribute to the pathology of neuroinflammatory disorders, reacting to inflammatory stimuli and undergoing distinct changes in both morphology and gene expression17 that can either limit or promote injury. The recruitment of inflammatory cells and modulation of the local inflammatory milieu implicate the astrocyte as an important regulator of neuroinflammation 18. As such, DMTs capable of influencing astrocyte activation may be beneficial in the context of MS. DMF has previously been demonstrated to reduce the activation of astrocytes, highlighting multiple potential mechanisms through which DMF may reduce neuroinflammation 11, 13.…”

Section: Introductionmentioning

confidence: 99%

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Effects of fumarates on inflammatory human astrocyte responses and oligodendrocyte differentiation

Galloway

Williams

Moore

2017

Ann Clin Transl Neurol

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ObjectiveDimethyl fumarate (DMF) is a fumaric acid ester approved for the treatment of relapsing‐remitting multiple sclerosis (RRMS). In both the brain and periphery, DMF and its metabolite monomethyl fumarate (MMF) exert anti‐inflammatory and antioxidant effects. Our aim was to compare the effects of DMF and MMF on inflammatory and antioxidant pathways within astrocytes, a critical supporting glial cell in the central nervous system (CNS). Direct effects of fumarates on neural progenitor cell (NPC) differentiation toward the oligodendrocyte lineage were also assessed.MethodsPrimary astrocyte cultures were derived from both murine and human brains. Following pretreatment with MMF, DMF, or vehicle, astrocytes were stimulated with IL‐1β for 24 h; gene and microRNA expression were measured by qPCR. Cytokine production and reactive oxygen species (ROS) generation were also measured. NPCs were differentiated into the oligodendrocyte lineage in the presence of fumarates and immunostained using early oligodendrocyte markers.ResultsIn both murine and human astrocytes, DMF, but not MMF, significantly reduced secretion of IL‐6, CXCL10, and CCL2; neither fumarate promoted a robust increase in antioxidant gene expression, although both MMF and DMF prevented intracellular ROS production. Pretreatment with fumarates reduced microRNAs ‐146a and ‐155 upon stimulation. In NPC cultures, DMF increased the number of O4+ and NG2+ cells.InterpretationThese results suggest that DMF, and to a lesser extent MMF, mediates the anti‐inflammatory effects within astrocytes. This is supported by recent observations that in the inflamed CNS, DMF may be the active compound mediating the anti‐inflammatory effects independent from altered antioxidant gene expression.

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Section: Discussionmentioning

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Effects of fumarates on inflammatory human astrocyte responses and oligodendrocyte differentiation

Galloway

Williams

Moore

2017

Ann Clin Transl Neurol

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“…During MS and EAE, proinflammatory monocytes are recruited to the CNS, where they play a central role in promoting neurodegeneration (2,36,37,39). Thus, chemotactic factors produced by astrocytes play an important role in promoting disease progression in MS (40,52,53). To address the effects of FTY720 on the recruitment of Ly6C hi proinflammatory monocytes by astrocytes we used an in vitro transwell migration assay.…”

Section: Astrocytic S1pr Controls Astrocyte Neurotoxicity and Monocytementioning

confidence: 99%

“…Astrocytes display neurotoxic activities in the context of chronic CNS inflammation and also induce and amplify pathogenic activities in microglia and monocytes recruited to the CNS (40,(45)(46)(47)(48)(49)(50)(51). Thus, to evaluate the relevance to disease pathogenesis of the effects of FTY720 on the transcriptional program of astrocytes, we analyzed the effects of FTY720 on the neurotoxic potential of astrocytes and on their ability to control migration and monocyte polarization (2).…”

Section: Astrocytic S1pr Controls Astrocyte Neurotoxicity and Monocytementioning

confidence: 99%

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

Rothhammer

Kenison

Tjon

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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160

147

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Multiple sclerosis (MS) is an autoimmune inflammatory demyelinating disease of the CNS that causes disability in young adults as a result of the irreversible accumulation of neurological deficits. Although there are potent disease-modifying agents for its initial relapsing-remitting phase, these therapies show limited efficacy in secondary progressive MS (SPMS). Thus, there is an unmet clinical need for the identification of disease mechanisms and potential therapeutic approaches for SPMS. Here, we show that the sphingosine 1-phosphate receptor (S1PR) modulator fingolimod (FTY720) ameliorated chronic progressive experimental autoimmune encephalomyelitis in nonobese diabetic mice, an experimental model that resembles several aspects of SPMS, including neurodegeneration and disease progression driven by the innate immune response in the CNS. Indeed, S1PR modulation by FTY720 in murine and human astrocytes suppressed neurodegeneration-promoting mechanisms mediated by astrocytes, microglia, and CNS-infiltrating proinflammatory monocytes. Genome-wide studies showed that FTY720 suppresses transcriptional programs associated with the promotion of disease progression by astrocytes. The study of the molecular mechanisms controlling these transcriptional modules may open new avenues for the development of therapeutic strategies for progressive MS.multiple sclerosis | sphingolipid metabolism | astrocytes | EAE | secondary progression M ultiple sclerosis (MS) is a chronic autoimmune disease of the CNS that, in most patients, initially presents with a relapsing-remitting course. This relapsing-remitting stage is often followed by a secondary progressive phase characterized by the progressive and irreversible accumulation of neurological deficits. The available therapeutic approaches for relapsing-remitting MS (RRMS) show limited efficacy in secondary progressive MS (SPMS), reflecting our insufficient understanding of the pathologic mechanisms that drive disease progression in SPMS and primary progressive MS (1). 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 (1-6). 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) 1-5] 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 (7-12). FTY720 (fingolimod) is a modulator of S1P receptors 1, 3, 4, and 5 with therapeutic effects on RRMS (13-18). The therapeutic effects of ...

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“…Astrocytes are the predominant glial cell in the CNS and are important for the regulation of metabolism, for the modulation of neuronal transmission, and for CNS development and repair, among other functions (1)(2)(3)(4)(5)(6). Astrocytes also are involved in the response to CNS injury and disease, and they are thought to participate in the pathogenesis of multiple sclerosis (MS) in humans and in the development of MS-like disease in animal models of experimental autoimmune encephalomyelitis (EAE) (7). Another essential function of astrocytes in health and disease is the control of the blood-brain barrier (BBB), which regulates the passage of blood leukocytes and molecules into the CNS (8,9).…”

Section: Introductionmentioning

confidence: 99%

Control of autoimmune CNS inflammation by astrocytes

Cited by 157 publications

References 137 publications

Effects of fumarates on inflammatory human astrocyte responses and oligodendrocyte differentiation

Effects of fumarates on inflammatory human astrocyte responses and oligodendrocyte differentiation

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

Astrocytes to the rescue! Glia limitans astrocytic endfeet control CNS inflammation

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