Myelin repair is accelerated by inactivating CXCR2 on nonhematopoietic cells.
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS and remyelination in MS ultimately fails. Although strategies to promote myelin repair are eagerly sought, mechanisms underlying remyelination in vivo have been elusive. CXCR2 is expressed on neutrophils and oligodendrocyte lineage cells in the CNS. CXCR2-positive neutrophils facilitate inflammatory demyelination in demyelination models such as experimental autoimmune encephalomyelitis (EAE) and cuprizone intoxication. Systemic injection of a small molecule CXCR2 antagonist at the onset of EAE decreased demyelinated lesions. These results left the cellular target of the CXCR2 antagonist uncertain and did not clarify whether CXCR2 blockade prevented demyelination or promoted remyelination. Here, we show that the actions of CXCR2 on nonhematopoietic cells unexpectedly delay myelin repair. Bone marrow chimeric mice (Cxcr2(+/-)-->Cxcr2(-/-) and Cxcr2(+/-)-->Cxcr2(+/+)) were subjected to two distinct models of myelin injury. In all cases, myelin repair was more efficient in Cxcr2(+/-)-->Cxcr2(-/-) animals. Oligodendrocyte progenitor cells (OPCs) in demyelinated lesions of Cxcr2(+/-)-->Cxcr2(-/-) mice proliferated earlier and more vigorously than in tissues from Cxcr2(+/-)--> Cxcr2(+/+) animals. In vitro demyelinated CNS slice cultures also showed better myelin repair when CXCR2 was blocked with neutralizing antibodies or was genetically deleted. Our results suggest that CXCR2 inactivation permits optimal spatiotemporal positioning of OPCs in demyelinating lesions to receive local proliferative and differentiating signals. Given that CXCR2 exerts dual functions that promote demyelination and decrease remyelination by actions toward hematopoietic cells and nonhematopoietic cells, respectively, our findings identify CXCR2 as a promising drug target for clinical demyelinating disorders.
Liu
LiPing
L
Neuroinflammation Research Centre, Department of Neuroscience, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA.
Darnall
Lindsey
L
Hu
Taofang
T
Choi
Karen
K
Lane
Thomas E
TE
Ransohoff
Richard M
RM
D000818:Animals; D000831:Animals, Newborn; D000906:Antibodies / Q000494:pharmacology; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D002531:Cerebellum / Q000187:drug effects; D003471:Cuprizone; D003711:Demyelinating Diseases / Q000139:chemically induced / Q000276:immunology; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology*; D005434:Flow Cytometry; D005620:Freund's Adjuvant / Q000009:adverse effects; D006023:Glycoproteins / Q000009:adverse effects; D066298:In Vitro Techniques; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008070:Lipopolysaccharides / Q000009:adverse effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission / Q000379:methods; D004676:Myelin Basic Protein / Q000235:genetics / Q000378:metabolism; D018991:Myelin Proteolipid Protein / Q000009:adverse effects; D009186:Myelin Sheath / Q000502:physiology* / Q000648:ultrastructure; D063308:Myelin-Oligodendrocyte Glycoprotein; D009416:Nerve Regeneration / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D009460:Neurologic Examination; D009836:Oligodendroglia / Q000187:drug effects / Q000502:physiology; D010446:Peptide Fragments / Q000009:adverse effects; D010852:Picrotoxin / Q000494:pharmacology; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D020127:Recovery of Function / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D012720:Severity of Illness Index; D013234:Stem Cells / Q000187:drug effects; D013997:Time Factors
D000906:Antibodies; D000697:Central Nervous System Stimulants; D003471:Cuprizone; D005620:Freund's Adjuvant; D006023:Glycoproteins; D017493:Leukocyte Common Antigens; D008070:Lipopolysaccharides; D004676:Myelin Basic Protein; D018991:Myelin Proteolipid Protein; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D010852:Picrotoxin; D018809:Proliferating Cell Nuclear Antigen; D023063:Receptors, Interleukin-8B; C445081:myelin oligodendrocyte glycoprotein (35-55); C435023:myelin proteolipid protein (139-151)