TY - JOUR
T1 - Activation of necroptosis in multiple sclerosis
AU - Ofengeim, Dimitry
AU - Ito, Yasushi
AU - Najafov, Ayaz
AU - Zhang, Yaoyang
AU - Shan, Bing
AU - DeWitt, Judy Park
AU - Ye, Juanying
AU - Zhang, Xumin
AU - Chang, Ansi
AU - Vakifahmetoglu-Norberg, Helin
AU - Geng, Jiefei
AU - Py, Benedicte
AU - Zhou, Wen
AU - Amin, Palak
AU - Lima, Jonilson Berlink
AU - Qi, Chunting
AU - Yu, Qiang
AU - Trapp, Bruce
AU - Yuan, Junying
N1 - Publisher Copyright:
© 2015 The Authors.
PY - 2015/3/24
Y1 - 2015/3/24
N2 - Multiple sclerosis (MS), a common neurodegenerative disease of the CNS, is characterized by the loss of oligodendrocytes and demyelination. Tumor necrosis factor α (TNF-α), a proinflammatory cytokine implicated in MS, can activate necroptosis, a necrotic cell death pathway regulated by RIPK1 and RIPK3 under caspase-8-deficient conditions. Here, we demonstrate defective caspase-8 activation, as well as activation of RIPK1, RIPK3, and MLKL, the hallmark mediators of necroptosis, in the cortical lesions of human MS pathological samples. Furthermore, we show that MS pathological samples are characterized by an increased insoluble proteome in common with other neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Finally, we show that necroptosis mediates oligodendrocyte degeneration induced by TNF-α and that inhibition of RIPK1 protects against oligodendrocyte cell death in two animal models of MS and in culture. Our findings demonstrate that necroptosis is involved in MS andsuggest that targeting RIPK1 may represent a therapeutic strategy for MS.
AB - Multiple sclerosis (MS), a common neurodegenerative disease of the CNS, is characterized by the loss of oligodendrocytes and demyelination. Tumor necrosis factor α (TNF-α), a proinflammatory cytokine implicated in MS, can activate necroptosis, a necrotic cell death pathway regulated by RIPK1 and RIPK3 under caspase-8-deficient conditions. Here, we demonstrate defective caspase-8 activation, as well as activation of RIPK1, RIPK3, and MLKL, the hallmark mediators of necroptosis, in the cortical lesions of human MS pathological samples. Furthermore, we show that MS pathological samples are characterized by an increased insoluble proteome in common with other neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Finally, we show that necroptosis mediates oligodendrocyte degeneration induced by TNF-α and that inhibition of RIPK1 protects against oligodendrocyte cell death in two animal models of MS and in culture. Our findings demonstrate that necroptosis is involved in MS andsuggest that targeting RIPK1 may represent a therapeutic strategy for MS.
UR - http://www.scopus.com/inward/record.url?scp=84925677956&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84925677956&partnerID=8YFLogxK
U2 - 10.1016/j.celrep.2015.02.051
DO - 10.1016/j.celrep.2015.02.051
M3 - Article
C2 - 25801023
AN - SCOPUS:84925677956
SN - 2211-1247
VL - 10
SP - 1836
EP - 1849
JO - Cell Reports
JF - Cell Reports
IS - 11
ER -