RIPK1 Activation Mediates Neuroinflammation and Disease Progression in Multiple Sclerosis

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2021 May 12

PMID 33979622

Citations 43

Authors

Matija Zelic

Fabrizio Pontarelli

Lisa Woodworth

Cheng Zhu

Amy Mahan

Yi Ren

Michael LaMorte

Ross Gruber

Aislinn Keane

Pequita Loring

Lilu Guo

Tai-He Xia

Boyao Zhang

Pontus Orning

Egil Lien

Alexei Degterev

Timothy Hammond

Dimitry Ofengeim

Affiliations

Soon will be listed here.

Abstract

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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