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RIPK1 activation mediates neuroinflammation and disease progression in multiple sclerosis

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 pro...

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Autores principales: Zelic, Matija, Pontarelli, Fabrizio, Woodworth, Lisa, Zhu, Cheng, Mahan, Amy, Ren, Yi, LaMorte, Michael, Gruber, Ross, Keane, Aislinn, Loring, Pequita, Guo, Lilu, Xia, Tai-he, Zhang, Boyao, Orning, Pontus, Lien, Egil, Degterev, Alexei, Hammond, Timothy, Ofengeim, Dimitry
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8917516/
https://www.ncbi.nlm.nih.gov/pubmed/33979622
http://dx.doi.org/10.1016/j.celrep.2021.109112
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author Zelic, Matija
Pontarelli, Fabrizio
Woodworth, Lisa
Zhu, Cheng
Mahan, Amy
Ren, Yi
LaMorte, Michael
Gruber, Ross
Keane, Aislinn
Loring, Pequita
Guo, Lilu
Xia, Tai-he
Zhang, Boyao
Orning, Pontus
Lien, Egil
Degterev, Alexei
Hammond, Timothy
Ofengeim, Dimitry
author_facet Zelic, Matija
Pontarelli, Fabrizio
Woodworth, Lisa
Zhu, Cheng
Mahan, Amy
Ren, Yi
LaMorte, Michael
Gruber, Ross
Keane, Aislinn
Loring, Pequita
Guo, Lilu
Xia, Tai-he
Zhang, Boyao
Orning, Pontus
Lien, Egil
Degterev, Alexei
Hammond, Timothy
Ofengeim, Dimitry
author_sort Zelic, Matija
collection PubMed
description 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.
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spelling pubmed-89175162022-03-12 RIPK1 activation mediates neuroinflammation and disease progression in multiple sclerosis Zelic, Matija Pontarelli, Fabrizio Woodworth, Lisa Zhu, Cheng Mahan, Amy Ren, Yi LaMorte, Michael Gruber, Ross Keane, Aislinn Loring, Pequita Guo, Lilu Xia, Tai-he Zhang, Boyao Orning, Pontus Lien, Egil Degterev, Alexei Hammond, Timothy Ofengeim, Dimitry Cell Rep Article 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. 2021-05-11 /pmc/articles/PMC8917516/ /pubmed/33979622 http://dx.doi.org/10.1016/j.celrep.2021.109112 Text en https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ).
spellingShingle Article
Zelic, Matija
Pontarelli, Fabrizio
Woodworth, Lisa
Zhu, Cheng
Mahan, Amy
Ren, Yi
LaMorte, Michael
Gruber, Ross
Keane, Aislinn
Loring, Pequita
Guo, Lilu
Xia, Tai-he
Zhang, Boyao
Orning, Pontus
Lien, Egil
Degterev, Alexei
Hammond, Timothy
Ofengeim, Dimitry
RIPK1 activation mediates neuroinflammation and disease progression in multiple sclerosis
title RIPK1 activation mediates neuroinflammation and disease progression in multiple sclerosis
title_full RIPK1 activation mediates neuroinflammation and disease progression in multiple sclerosis
title_fullStr RIPK1 activation mediates neuroinflammation and disease progression in multiple sclerosis
title_full_unstemmed RIPK1 activation mediates neuroinflammation and disease progression in multiple sclerosis
title_short RIPK1 activation mediates neuroinflammation and disease progression in multiple sclerosis
title_sort ripk1 activation mediates neuroinflammation and disease progression in multiple sclerosis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8917516/
https://www.ncbi.nlm.nih.gov/pubmed/33979622
http://dx.doi.org/10.1016/j.celrep.2021.109112
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