Caspase-11 mediates oligodendrocyte cell death and pathogenesis of autoimmune-mediated demyelination.
Multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are inflammatory diseases of the central nervous system (CNS) characterized by localized areas of demyelination. The mechanisms underlying oligodendrocyte (OLG) injury in MS and EAE remain unknown. Here we show that caspase-11 plays crucial roles in OLG death and pathogenesis in EAE. Caspase-11 and activated caspase-3 were both expressed in OLGs in spinal cord EAE lesions. OLGs from caspase-11-deficient mice were highly resistant to the cell death induced by cytotoxic cytokines. EAE susceptibility and cytokine concentrations in the CNS were significantly reduced in caspase-11-deficient mice. Our findings suggest that OLG death is mediated by a pathway that involves caspases-11 and -3 and leads to the demyelination observed in EAE.
Hisahara
S
S
Division of Neuroanatomy, Department of Neuroscience, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.
Yuan
J
J
Momoi
T
T
Okano
H
H
Miura
M
M
D000818:Animals; D017209:Apoptosis; D001483:Base Sequence; D053148:Caspase 3; D020169:Caspases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D053471:Caspases, Initiator; D017931:DNA Primers / Q000235:genetics; D003711:Demyelinating Diseases / Q000209:etiology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology / Q000209:etiology* / Q000276:immunology; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000209:etiology; D009836:Oligodendroglia / Q000166:cytology* / Q000201:enzymology* / Q000276:immunology; D011247:Pregnancy; D013116:Spinal Cord / Q000201:enzymology
D017931:DNA Primers; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; C101136:Casp4 protein, mouse; D053148:Caspase 3; D020169:Caspases; D053471:Caspases, Initiator