| Title | RIP1 kinase inhibitor halts the progression of an immune-induced demyelination disease at the stage of monocyte elevation |
| Authors | Zhang, Sitao Su, Yaning Ying, Zhengxin Guo, Dejia Pan, Chenjie Guo, Jia Zou, Ziye Wang, Lei Zhang, Ze Jiang, Zhaodi Zhang, Zhiyuan Wang, Xiaodong |
| Affiliation | Peking Univ, Sch Life Sci, Beijing 100871, Peoples R China Natl Inst Biol Sci, Zhongguancun Life Sci Pk, Beijing 102206, Peoples R China Tsinghua Univ, Tsinghua Inst Multidisciplinary Biomed Res, Beijing 102206, Peoples R China Tsinghua Univ, Sch Life Sci, Beijing 100084, Peoples R China |
| Keywords | RIP1 kinase myelin demyelination multiple sclerosis MLKL |
| Issue Date | 2019 |
| Publisher | PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA |
| Abstract | 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 domainlike 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. |
| URI | http://hdl.handle.net/20.500.11897/549864 |
| ISSN | 0027-8424 |
| DOI | 10.1073/pnas.1819917116 |
| Indexed | SCI(E) |
| Appears in Collections: | 生命科学学院 |
