Chemokine receptor inhibition by AMD3100 is strictly confined to CXCR4

Hatse, Sigrid; Princen, Katrien; Bridger, Gary; Clercq, Erik De; Schols, Dominique

doi:10.1016/s0014-5793(02)03143-5

Cited by 415 publications

(373 citation statements)

References 31 publications

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“…Because higher numbers of CXCR4+NG2+ cells were detected within the CC of mice after 6 wk of CPZ ingestion compared with control mice, a time-point when accumulated OPCs will commence remyelination if CPZ feeding ceases, we hypothesized that CXCL12 mediates the differentiation of OPCs into mature oligodendrocytes. To test this, we treated CPZexposed mice with the CXCR4 antagonist AMD3100, which specifically inhibits binding of CXCL12 to CXCR4 (23). AMD 3100, which has a plasma half-life of 0.9 h in rodents after i.p.…”

Section: Cxcr4 Antagonism Prevents Remyelination Within the CC After mentioning

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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Section: Cxcr4 Antagonism Prevents Remyelination Within the CC After mentioning

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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“…135 Plerixafor Plerixafor (AMD3100, Genzyme Corporation, Cambridge, MA, USA) is a selective and reversible antagonist of CXCR4 and disrupts its interaction with SDF-1, thereby releasing hematopoietic stem cells into the circulation. [136][137][138] Plerixafor used in conjunction with G-CSF has been shown in a phase 2 study to quickly and predictably enhance the numbers of CD34 þ cells circulating in the peripheral blood. 139 In this study, patients with NHL mobilized more CD34 þ cells per day of apheresis after administration of plerixafor plus G-CSF than after administration of G-CSF alone (median increase of 4.4-fold (range: 1.1-to 54.4-fold)).…”

Section: Novel Agentsmentioning

confidence: 99%

Improving stem cell mobilization strategies: future directions

Bensinger

DiPersio

McCarty

2009

Bone Marrow Transplant

202

209

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“…Because the killing of P. gingivalis by mouse phagocytes is mediated by NO (18), we first determined whether CXCR4 inhibits induction of NO (measured as NO 2 Ϫ , its stable metabolite) by P. gingivalis in mouse macrophages. Indeed, CXCR4 blockade with AMD3100 [highly specific antagonist of both human and mouse CXCR4 (19,20)] or anti-CXCR4 mAb resulted in significantly enhanced levels of NO 2 Ϫ (Fig. 6A), the production of which depended heavily on TLR2 (Fig.…”

Section: P Gingivalis Exploits Cxcr4 In Vitro and In Vivo To Promotementioning

confidence: 99%

Pathogen induction of CXCR4/TLR2 cross-talk impairs host defense function

Hajishengallis

Wang²,

Liang³

et al. 2008

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

180

252

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We report a mechanism of microbial evasion of Toll-like receptor (TLR)-mediated immunity that depends on CXCR4 exploitation. Specifically, the oral/systemic pathogen Porphyromonas gingivalis induces cross-talk between CXCR4 and TLR2 in human monocytes or mouse macrophages and undermines host defense. This is accomplished through its surface fimbriae, which induce CXCR4/TLR2 coassociation in lipid rafts and interact with both receptors: Binding to CXCR4 induces cAMP-dependent protein kinase A (PKA) signaling, which in turn inhibits TLR2-mediated proinflammatory and antimicrobial responses to the pathogen. This outcome enables P. gingivalis to resist clearance in vitro and in vivo and thus to promote its adaptive fitness. However, a specific CXCR4 antagonist abrogates this immune evasion mechanism and offers a promising counterstrategy for the control of P. gingivalis periodontal or systemic infections.bacterial pathogenesis ͉ immune evasion ͉ macrophages ͉ P. gingivalis ͉ protein kinase A

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Chemokine receptor inhibition by AMD3100 is strictly confined to CXCR4

Cited by 415 publications

References 31 publications

CXCR4 promotes differentiation of oligodendrocyte progenitors and remyelination

CXCR4 promotes differentiation of oligodendrocyte progenitors and remyelination

Improving stem cell mobilization strategies: future directions

Pathogen induction of CXCR4/TLR2 cross-talk impairs host defense function

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