Program in Innate Immunity, Division of Infectious Diseases and Immunology, Department of Medicine; Graduate School of Biomedical Sciences
Cell Biology | Cells | Enzymes and Coenzymes | Immune System Diseases | Molecular and Cellular Neuroscience | Nervous System Diseases
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.
RIPK1, astrocyte, cell death, inflammation, microglia, multiple sclerosis, necroptosis
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Copyright 2021 The Author(s). This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
DOI of Published Version
Zelic M, Pontarelli F, Woodworth L, Zhu C, Mahan A, Ren Y, LaMorte M, Gruber R, Keane A, Loring P, Guo L, Xia TH, Zhang B, Orning P, Lien E, Degterev A, Hammond T, Ofengeim D. RIPK1 activation mediates neuroinflammation and disease progression in multiple sclerosis. Cell Rep. 2021 May 11;35(6):109112. doi: 10.1016/j.celrep.2021.109112. PMID: 33979622. Link to article on publisher's site
Zelic M, Zhang B, Orning MA, Lien E, Ofengeim D. (2021). RIPK1 activation mediates neuroinflammation and disease progression in multiple sclerosis. Open Access Publications by UMMS Authors. https://doi.org/10.1016/j.celrep.2021.109112. Retrieved from https://escholarship.umassmed.edu/oapubs/4718
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This work is licensed under a Creative Commons Attribution 4.0 License.