CXCR2-positive neutrophils are essential for cuprizone-induced demyelination: relevance to multiple sclerosis.
Multiple sclerosis is an inflammatory demyelinating disorder of the CNS. Recent studies have suggested diverse mechanisms as underlying demyelination, including a subset of lesions induced by an interaction between metabolic insult to oligodendrocytes and inflammatory mediators. For mice of susceptible strains, cuprizone feeding results in oligodendrocyte cell loss and demyelination of the corpus callosum. Remyelination ensues and has been extensively studied. Cuprizone-induced demyelination remains incompletely characterized. We found that mice lacking the type 2 CXC chemokine receptor (CXCR2) were relatively resistant to cuprizone-induced demyelination and that circulating CXCR2-positive neutrophils were important for cuprizone-induced demyelination. Our findings support a two-hit process of cuprizone-induced demyelination, supporting the idea that multiple sclerosis pathogenesis features extensive oligodendrocyte cell loss. These data suggest that cuprizone-induced demyelination is useful for modeling certain aspects of multiple sclerosis pathogenesis.
Neuroinflammation Research Center, Department of Neuroscience, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
LiPing
L
Liu
Abdelmadjid
A
Belkadi
Lindsey
L
Darnall
Taofang
T
Hu
Caitlin
C
Drescher
Anne C
AC
Cotleur
Dolly
D
Padovani-Claudio
Tao
T
He
Karen
K
Choi
Thomas E
TE
Lane
Robert H
RH
Miller
Richard M
RM
Ransohoff
D000818:Animals; D002678:Chimera; D003337:Corpus Callosum / Q000187:drug effects / Q000503:physiopathology / Q000648:ultrastructure; D003471:Cuprizone / Q000633:toxicity*; D003711:Demyelinating Diseases / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008996:Monoamine Oxidase Inhibitors / Q000633:toxicity*; D009103:Multiple Sclerosis / Q000503:physiopathology; D009185:Myelin Proteins / Q000378:metabolism; D009186:Myelin Sheath / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D009836:Oligodendroglia / Q000187:drug effects / Q000502:physiology / Q000648:ultrastructure; D012333:RNA, Messenger / Q000378:metabolism; D023063:Receptors, Interleukin-8B / Q000235:genetics / Q000378:metabolism*
D008996:Monoamine Oxidase Inhibitors; D009185:Myelin Proteins; D012333:RNA, Messenger; D023063:Receptors, Interleukin-8B; D003471:Cuprizone