A role for CXCL12 (SDF-1α) in the pathogenesis of multiple sclerosis: Regulation of CXCL12 expression in astrocytes by soluble myelin basic protein

Calderon, Tina M.; Eugenín, Eliseo A.; Lopez, Lillie; Kumar, Sridhar Sampath; Hesselgesser, Joseph; Raine, Cedric S.; Berman, Joan W.

doi:10.1016/j.jneuroim.2006.05.003

Cited by 156 publications

(122 citation statements)

References 59 publications

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“…HIF-1 and VEGF enhance the expression of CXCR4 in glioblastoma (Zagzag D et al, 2006). IL-1β induces CXCL12 in astrocytes by ERK and PI3K signaling pathways (Calderon TM et al, 2006;Peng H et al, 2006). Our lab demonstrated that CXCR4 expression by primary mouse astrocytes is suppressed by exposure to TNF-α (Han Y et al, 2001a).…”

Section: Inducible Expressionmentioning

confidence: 66%

Multiple roles of chemokine CXCL12 in the central nervous system: A migration from immunology to neurobiology

Ransohoff

2008

Progress in Neurobiology

303

245

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Chemotactic cytokines (chemokines) have been traditionally defined as small (10-14 kDa) secreted leukocyte chemoattractants. However, chemokines and their cognate receptors are constitutively expressed in the central nervous system (CNS) where immune activities are under stringent control. Why and how the CNS uses the chemokine system to carry out its complex physiological functions has intrigued neurobiologists. Here, we focus on chemokine CXCL12 and its receptor CXCR4 that have been widely characterized in peripheral tissues and delineate their main functions in the CNS. Extensive evidence supports CXCL12 as a key regulator for early development of the CNS. CXCR4 signaling is required for the migration of neuronal precursors, axon guidance/pathfinding and maintenance of neural progenitor cells (NPCs). In the mature CNS, CXCL12 modulates neurotransmission, neurotoxicity and neuroglial interactions. Thus, chemokines represent an inherent system that helps establish and maintain CNS homeostasis. In addition, growing evidence implicates altered expression of CXCL12 and CXCR4 in the pathogenesis of CNS disorders such as HIVassociated encephalopathy, brain tumor, stroke and multiple sclerosis (MS), making them the plausible targets for future pharmacological intervention.

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Section: Inducible Expressionmentioning

confidence: 66%

Multiple roles of chemokine CXCL12 in the central nervous system: A migration from immunology to neurobiology

Ransohoff

2008

Progress in Neurobiology

303

245

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“…Several in vitro studies suggest that CXCR4-expressing OPCs exhibit chemotactic and maturational responses to CXCL12, which promotes their expression of myelin proteins and differentiation into oligodendrocytes (17,18). Additional studies have shown that exposure to myelin basic protein leads to up-regulation of CXCL12 within astrocytes in vitro (29), implicating oligodendrocyte injury in glial CXCL12 expression. Our data demonstrating that CXCL12-mediated CXCR4 activation is required for myelin production by differentiating OPCs is consistent with proposed roles for these molecules during developmental myelination.…”

Section: Discussionmentioning

confidence: 99%

“…Sources of CXCL12 in the normal adult CNS include neurons, endothelial cells, and meninges (13,15,25), whereas astrocyte expression of CXCL12 has been observed only in several pathological states including MS, HIV-1 encephalitis, and malignancy (29,(31)(32)(33). In studies of MS tissues, CXCL12 expression is observed within activated astrocytes in both silent and active MS lesions (34), suggesting its expression occurs in response to injury.…”

Section: Discussionmentioning

confidence: 99%

CXCR4 promotes differentiation of oligodendrocyte progenitors and remyelination

Patel

McCandless

Dorsey

et al. 2010

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

204

206

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Multiple sclerosis is a neurodegenerative disease characterized by episodes of autoimmune attack of oligodendrocytes leading to demyelination and progressive functional deficits. Because many patients exhibit functional recovery in between demyelinating episodes, understanding mechanisms responsible for repair of damaged myelin is critical for developing therapies that promote remyelination and prevent disease progression. The chemokine CXCL12 is a developmental molecule known to orchestrate the migration, proliferation, and differentiation of neuronal precursor cells within the developing CNS. Although studies suggest a role for CXCL12 in oligodendroglia ontogeny in vitro, no studies have investigated the role of CXCL12 in remyelination in vivo in the adult CNS. Using an experimental murine model of demyelination mediated by the copper chelator cuprizone, we evaluated the expression of CXCL12 and its receptor, CXCR4, within the demyelinating and remyelinating corpus callosum (CC). CXCL12 was significantly up-regulated within activated astrocytes and microglia in the CC during demyelination, as were numbers of CXCR4+ NG2+ oligodendrocyte precursor cells (OPCs). Loss of CXCR4 signaling via either pharmacological blockade or in vivo RNA silencing led to decreased OPCs maturation and failure to remyelinate. These data indicate that CXCR4 activation, by promoting the differentiation of OPCs into oligodendrocytes, is critical for remyelination of the injured adult CNS.M ultiple sclerosis (MS), a progressive, neurodegenerative disease of the CNS, occurs most often in a relapsing/remitting form, in which a period of demyelination is followed by a period of functional recovery (1). The recovery stage involves remyelination via the migration and maturation of oligodendrocyte precursor cells (OPCs) (2). However, as the disease progresses, remyelination fails with continuous loss of function (3). Possible explanations for remyelination failure of intact axons include defects in OPC recruitment to the site of demyelination or in OPC differentiation into myelinating oligodendrocytes. Although studies indicate that both aspects of OPC biology are altered in MS (4, 5), the molecular mechanisms that orchestrate these processes within the adult CNS are incompletely understood.Studies in mice indicate that neural precursors that give rise to cells of oligodendrocytes lineage can be identified within the ventral half of the ventricular zones of all CNS regions by embryonic days 12-14 (E12-E14) via their expression of NG2 chondroitin sulfate proteoglycan (6). In the final stage of oligodendrocyte differentiation, which occurs primarily during the postnatal period (P4-P12), OPCs begin to express mature markers of oligodendrocytes including 2′3′-cyclic nucleotide phosphohydrolase (CNPase), myelin basic protein (MBP), proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG). Similar events occur during remyelination; NG2+ OPCs proliferate within subventricular zones, migrate to areas of demyelination, and differentiate ...

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“…Besides EAE (the present study), several other distinct models of brain disease, including stroke, trauma, Alzheimer's (Fumagalli et al, 2016) have been associated to persistent GPR17 upregulation and impaired progression along the oligodendrocyte lineage, eventually resulting in dysfunctional repair. Importantly, GPR17 has been shown to “promiscuously” respond to several different proinflammatory ligands accumulating at injury sites (Sensi et al, 2014; Parravicini et al, 2016), not only uracil nucleotides and cysteinyl‐leukotrienes (Ciana et al, 2006), but also oxysterols and CXCL12 (Parravicini et al, 2016), one of the most prominent chemokines in the lesions of multiple sclerosis patients (Calderon et al, 2006). In a permissive environment, these inflammatory stimuli could initially contribute to promotion of remyelination through GPR17 stimulation, in line with literature data proposing that acute inflammation triggers remyelination (Foote & Blakemore 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Our in vitro data suggest that GPR17 aberrant overexpression in OPCs leads to impaired downregulation at late differentiation stages and blockade of cells at immature stages, thus impairing remyelination (Fumagalli, Lecca, & Abbracchio, 2016). Initial data also suggest that GPR17 overexpression may be due, at least in part, to inflammatory cytokines and chemokines like the stromal derived factor 1 (SDF1), that accumulate at the sites of demyelinating inflamed lesions (Calderon et al, 2006) and can indeed specifically interact with this receptor (Parravicini et al, 2016). However, a detailed study on GPR17 dysfunction in in vivo conditions associated to demyelination and inflammation is still missing, nor is known whether changes in the pool of GPR17 + cells contribute to, or contrast, lesion repair.…”

Section: Introductionmentioning

confidence: 99%

Differential local tissue permissiveness influences the final fate of GPR17‐expressing oligodendrocyte precursors in two distinct models of demyelination

Coppolino

Marangon

Negri

et al. 2018

Glia

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Promoting remyelination is recognized as a novel strategy to foster repair in neurodegenerative demyelinating diseases, such as multiple sclerosis. In this respect, the receptor GPR17, recently emerged as a new target for remyelination, is expressed by early oligodendrocyte precursors (OPCs) and after a certain differentiation stage it has to be downregulated to allow progression to mature myelinating oligodendrocytes. Here, we took advantage of the first inducible GPR17 reporter mouse line (GPR17‐iCreERT2xCAG‐eGFP mice) allowing to follow the final fate of GPR17+ cells by tamoxifen‐induced GFP‐labeling to unveil the destiny of these cells in two demyelination models: experimental autoimmune encephalomyelitis (EAE), characterized by marked immune cell activation and inflammation, and cuprizone induced demyelination, where myelin dysfunction is achieved by a toxic insult. In both models, demyelination induced a strong increase of fluorescent GFP+ cells at damaged areas. However, only in the cuprizone model reacting GFP+ cells terminally differentiated to mature oligodendrocytes, thus contributing to remyelination. In EAE, GFP+ cells were blocked at immature stages and never became myelinating oligodendrocytes. We suggest these strikingly distinct fates be due to different permissiveness of the local CNS environment. Based on previously reported GPR17 activation by emergency signals (e.g., Stromal Derived Factor‐1), we propose that a marked inflammatory milieu, such as that reproduced in EAE, induces GPR17 overactivation resulting in impaired downregulation, untimely and prolonged permanence in OPCs, leading, in turn, to differentiation blockade. Combined treatments with remyelinating agents and anti‐inflammatory drugs may represent new potential adequate strategies to halt neurodegeneration and foster recovery.

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A role for CXCL12 (SDF-1α) in the pathogenesis of multiple sclerosis: Regulation of CXCL12 expression in astrocytes by soluble myelin basic protein

Cited by 156 publications

References 59 publications

Multiple roles of chemokine CXCL12 in the central nervous system: A migration from immunology to neurobiology

Multiple roles of chemokine CXCL12 in the central nervous system: A migration from immunology to neurobiology

CXCR4 promotes differentiation of oligodendrocyte progenitors and remyelination

Differential local tissue permissiveness influences the final fate of GPR17‐expressing oligodendrocyte precursors in two distinct models of demyelination

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