RIPK1 activation mediates neuroinflammation and disease progression in multiple sclerosis.

Cell reports 2021 May 11

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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. Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Citation

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. RIPK1 activation mediates neuroinflammation and disease progression in multiple sclerosis. Cell reports. 2021 May 11;35(6):109112