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广东福利彩票开奖中心:RIP1 kinase inhibitor halts the progression of an immune-induced demyelination disease at the stage of monocyte elevation
广东快乐十分投注下载 www.hmclip.net Edited by Tak W. Mak, The Campbell Family Institute for Breast Cancer Research at Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada, and approved January 31, 2019 (received for review November 26, 2018)
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Myelin sheaths insulate the neuronal axons and speed the transmission of electrical impulses. The demyelination process occurs in many human diseases, including multiple sclerosis (MS). Using multiple mouse models of MS, we demonstrate in this study the role of MLKL, a protein known to function in a form of regulated necrosis (necroptosis), in facilitating demyelination in a necroptosis-independent manner in the central nervous system. An RIP1 kinase inhibitor was shown to block the progression of MS in an immune-induced demyelination model, and it does so at the stage after antibody generation but before breakdown of the blood–brain barrier, at a likely step of monocyte elevation. These findings provide insights into the demyelination process and potential new therapeutic agents for MS.
Demyelination in the central nervous system (CNS) underlies many human diseases, including multiple sclerosis (MS). We report here the findings of our study of the CNS demyelination process using immune-induced [experimental autoimmune encephalomyelitis (EAE)] and chemical-induced [cuprizone (CPZ)] mouse models of demyelination. We found that necroptosis, a receptor-interacting protein 3 (RIP3) kinase and its substrate mixed lineage kinase domain-like protein (MLKL)-dependent cell death program, played no role in the demyelination process, whereas the MLKL-dependent, RIP3-independent function of MLKL in the demyelination process initially discovered in the peripheral nervous system in response to nerve injury, also functions in demyelination in the CNS in these models. Moreover, a receptor-interacting protein 1 (RIP1) kinase inhibitor, RIPA-56, blocked disease progression in the EAE-induced model but showed no effect in the CPZ-induced model. It does so most likely at a step of monocyte elevation downstream of T cell activation and myelin-specific antibody generation, although upstream of breakdown of the blood–brain barrier. RIP1-kinase dead knock-in mice shared a similar result as mice treated with the RIP1 inhibitor. These results indicate that RIP1 kinase inhibitor is a potential therapeutic agent for immune-mediated demyelination diseases that works by prevention of monocyte elevation, a function previously unknown for RIP1 kinase.
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Author contributions: S.Z. and X.W. designed research; S.Z., Y.S., Z.Y., D.G., C.P., J.G., Z.Z., L.W., Ze Zhang, and Z.J. performed research; Zhiyuan Zhang contributed new reagents/analytic tools; S.Z., Z.Y., C.P., and X.W. analyzed data; and S.Z. and X.W. wrote the paper.
Conflict of interest statement: X.W. and Zhiyuan Zhang are cofounders of a start-up company working on developing medicine for demyelination diseases.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1819917116/-/DCSupplemental.
Published under the PNAS license.