RIPK1 activation mediates neuroinflammation and disease progression in multiple sclerosis.
RIPK1
astrocyte
cell death
inflammation
microglia
multiple sclerosis
necroptosis
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
11 05 2021
11 05 2021
Historique:
received:
03
07
2020
revised:
27
02
2021
accepted:
20
04
2021
entrez:
12
5
2021
pubmed:
13
5
2021
medline:
10
2
2022
Statut:
ppublish
Résumé
Receptor interacting protein kinase 1 (RIPK1) mediates cell death and inflammatory signaling and is increased in multiple sclerosis (MS) brain samples. Here, we investigate the role of glial RIPK1 kinase activity in mediating MS pathogenesis. We demonstrate RIPK1 levels correlate with MS disease progression. We find microglia are susceptible to RIPK1-mediated cell death and identify an inflammatory gene signature that may contribute to the neuroinflammatory milieu in MS patients. We uncover a distinct role for RIPK1 in astrocytes in regulating inflammatory signaling in the absence of cell death and confirm RIPK1-kinase-dependent regulation in human glia. Using a murine MS model, we show RIPK1 inhibition attenuates disease progression and suppresses deleterious signaling in astrocytes and microglia. Our results suggest RIPK1 kinase activation in microglia and astrocytes induces a detrimental neuroinflammatory program that contributes to the neurodegenerative environment in progressive MS.
Identifiants
pubmed: 33979622
pii: S2211-1247(21)00446-0
doi: 10.1016/j.celrep.2021.109112
pmc: PMC8917516
mid: NIHMS1783515
pii:
doi:
Substances chimiques
Receptor-Interacting Protein Serine-Threonine Kinases
EC 2.7.11.1
Ripk1 protein, mouse
EC 2.7.11.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
109112Subventions
Organisme : NIA NIH HHS
ID : R56 AG058642
Pays : United States
Organisme : NINDS NIH HHS
ID : R21 NS111395
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI144400
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI146855
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI128547
Pays : United States
Informations de copyright
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests M.Z., F.P., L.W., C.Z., A.M., Y.R., M.L., R.G., L.G., P.L., T.X., T.H., and D.O. were employees of Sanofi at the time this research was conducted. The authors declare no other conflicts of interest.
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