title: Inhibition of CXCR2 signaling promotes recovery in models of multiple sclerosis.
abstract: Multiple sclerosis (MS) is a neurodegenerative disease characterized by demyelination/remyelination episodes that ultimately fail. Chemokines and their receptors have been implicated in both myelination and remyelination failure. Chemokines regulate migration, proliferation and differentiation of immune and neural cells during development and pathology. Previous studies have demonstrated that the absence of the chemokine receptor CXCR2 results in both disruption of early oligodendrocyte development and long-term structural alterations in myelination. Histological studies suggest that CXCL1, the primary ligand for CXCR2, is upregulated around the peripheral areas of demyelination suggesting that this receptor/ligand combination modulates responses to injury. Here we show that in focal LPC-induced demyelinating lesions, localized inhibition of CXCR2 signaling reduced lesion size and enhanced remyelination while systemic treatments were relatively less effective. Treatment of spinal cord cultures with CXCR2 antagonists reduced CXCL1 induced A2B5+ cell proliferation and increased differentiation of myelin producing cells. More critically, treatment of myelin oligodendrocyte glycoprotein peptide 35-55-induced EAE mice, an animal model of multiple sclerosis, with small molecule antagonists against CXCR2 results in increased functionality, decreased lesion load, and enhanced remyelination. Our findings demonstrate the importance of antagonizing CXCR2 in enhancing myelin repair by reducing lesion load and functionality in models of multiple sclerosis and thus providing a therapeutic target for demyelinating diseases.
authors.affiliation: Department of Neurosciences and Center for Translational Neuroscience, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: A E
authors.initials: AE
authors.lastname: Kerstetter
authors.forename: D A
authors.initials: DA
authors.lastname: Padovani-Claudio
authors.forename: L
authors.initials: L
authors.lastname: Bai
authors.forename: R H
authors.initials: RH
authors.lastname: Miller
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology / Q000627:therapeutic use; D001369:Axons / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D054360:Chemokine CXCL1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D005260:Female; D006023:Glycoproteins / Q000276:immunology / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology* / Q000503:physiopathology; D009186:Myelin Sheath / Q000187:drug effects* / Q000276:immunology* / Q000473:pathology; D063308:Myelin-Oligodendrocyte Glycoprotein; D009836:Oligodendroglia / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010446:Peptide Fragments / Q000276:immunology / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects / Q000276:immunology; D013116:Spinal Cord / Q000187:drug effects* / Q000276:immunology / Q000503:physiopathology; D014855:Wallerian Degeneration / Q000188:drug therapy / Q000276:immunology / Q000473:pathology
chemical_list: D000906:Antibodies; D054360:Chemokine CXCL1; D006023:Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D023063:Receptors, Interleukin-8B; C445081:myelin oligodendrocyte glycoprotein (35-55)