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 C.; Keane, Aislinn; Loring, P; Guo, Lilu; Xia, Tai-he; Zhang, Boyao; Orning, Pontus; Lien, Egil; Degterev, Alexei; Hammond, Timothy R.; Ofengeim, Dimitry

doi:10.1016/j.celrep.2021.109112

Cited by 78 publications

(74 citation statements)

References 70 publications

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“…For RIPK inhibition, a specific RIPK1 inhibitor (GSK′547, RA15777187) 64 , 65 was suspended in 0.6% methyl cellulose and mice were treated with 60 mg per kg body weight every 12 h by oral gavage. For control treatment we used methyl cellulose.…”

Section: Methodsmentioning

confidence: 99%

The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells

et al. 2021

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Coronavirus disease 2019 (COVID-19) can damage cerebral small vessels and cause neurological symptoms. Here we describe structural changes in cerebral small vessels of patients with COVID-19 and elucidate potential mechanisms underlying the vascular pathology. In brains of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individuals and animal models, we found an increased number of empty basement membrane tubes, so-called string vessels representing remnants of lost capillaries. We obtained evidence that brain endothelial cells are infected and that the main protease of SARS-CoV-2 (Mpro) cleaves NEMO, the essential modulator of nuclear factor-κB. By ablating NEMO, Mpro induces the death of human brain endothelial cells and the occurrence of string vessels in mice. Deletion of receptor-interacting protein kinase (RIPK) 3, a mediator of regulated cell death, blocks the vessel rarefaction and disruption of the blood–brain barrier due to NEMO ablation. Importantly, a pharmacological inhibitor of RIPK signaling prevented the Mpro-induced microvascular pathology. Our data suggest RIPK as a potential therapeutic target to treat the neuropathology of COVID-19.

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Section: Methodsmentioning

confidence: 99%

The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells

et al. 2021

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“…Comparison of transcriptome signatures between COVID-19 brains and chronic CNS diseases (including MS) revealed a significant intersection of dysregulated genes, particularly in glial cells. A notable example comes from RIPK1, whose overactivation in microglia and astrocytes contributes to MS pathology, particularly in the progressive disease (31). Moreover, COVID-19 differentially expressed genes are enriched with GWAS-associated variants of complex neurological traits, suggesting a possible interaction of the novel Coronavirus to the initiation or perpetuation of CNS disorders in individuals who are at risk (27).…”

Section: Sars-cov-2 and Neuroinflammationmentioning

confidence: 99%

Multiple Sclerosis and SARS-CoV-2: Has the Interplay Started?

et al. 2021

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Current knowledge on Multiple Sclerosis (MS) etiopathogenesis encompasses complex interactions between the host’s genetic background and several environmental factors that result in dysimmunity against the central nervous system. An old-aged association exists between MS and viral infections, capable of triggering and sustaining neuroinflammation through direct and indirect mechanisms. The novel Coronavirus, SARS-CoV-2, has a remarkable, and still not fully understood, impact on the immune system: the occurrence and severity of both acute COVID-19 and post-infectious chronic illness (long COVID-19) largely depends on the host’s response to the infection, that echoes several aspects of MS pathobiology. Furthermore, other MS-associated viruses, such as the Epstein-Barr Virus (EBV) and Human Endogenous Retroviruses (HERVs), may enhance a mechanistic interplay with the novel Coronavirus, with the potential to interfere in MS natural history. Studies on COVID-19 in people with MS have helped clinicians in adjusting therapeutic strategies during the pandemic; similar efforts are being made for SARS-CoV-2 vaccination campaigns. In this Review, we look over 18 months of SARS-CoV-2 pandemic from the perspective of MS: we dissect neuroinflammatory and demyelinating mechanisms associated with COVID-19, summarize pathophysiological crossroads between MS and SARS-CoV-2 infection, and discuss present evidence on COVID-19 and its vaccination in people with MS.

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“…RIPK1, a key mediator of necroptosis, controls inflammation and cell death via its kinase domain [ 28 ], and mediates the multimodal signaling pathways downstream to TNFR1 [ 29 ]. Since RIPK1 activation and necroptosis have been genetically and mechanistically linked with human neurodegenerative diseases such as MS [ 8 , 9 , 14 ], ALS [ 18 ] and Alzheimer’s disease (AD) [ 30 , 31 ], keen interests have been sparkled on developing CNS-penetrant new RIPK1 inhibitors as drug candidates to treat CNS diseases [ 17 ]. RIPK1 inhibitors, such as GSK2982772 [ 32 ] and DNL747 [ 33 ], have successfully completed their phase II clinical trials [ 12 ], warranting the safety and displaying their effectiveness in human subjects.…”

Section: Discussionmentioning

confidence: 99%

“…The level of tumor necrosis factor alpha (TNFα), the ligand for necroptosis, is elevated in the serum, brain and cerebral spinal fluid of MS patients, and the hallmark mediators of necroptosis including receptor interacting serine/threonine protein kinase 1 (RIPK1) are activated in both mature oligodendrocytes [ 8 ] and neurons [ 9 ] within demyelinated lesion of both animal models and MS patients. Importantly, inhibiting necroptosis by Nec-1s, so far the most potent inhibitor of RIPK1 activity [ 10 – 12 ], protects mature oligodendrocytes from death [ 8 , 13 ] and attenuates symptoms in a MS mouse model [ 14 ], indicating that inhibiting RIPK1 activity both protects myelin from demyelination and reduces neuroinflammation [ 8 , 9 , 14 ]. However, it is unknown whether inhibiting RIPK1 activity directly affect OPCs, the central player of remyelination.…”

Section: Introductionmentioning

confidence: 99%

Inhibition of RIPK1 by ZJU-37 promotes oligodendrocyte progenitor proliferation and remyelination via NF-κB pathway

Yang

Zheng

et al. 2022

Cell Death Discov.

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Receptor interacting serine/threonine protein kinase 1 (RIPK1) activation and necroptosis have been genetically and mechanistically linked with human multiple sclerosis and neurodegenerative diseases for which demyelination is a common key pathology. Demyelination can be healed through remyelination which is mediated by new oligodendrocytes derived from the adult oligodendrocyte progenitor cells (OPCs). Unfortunately, the efficiency of remyelination declines with progressive aging partially due to the depletion of OPCs following chronic or repeated demyelination. However, to our knowledge, so far there is no drug which enhances proliferation of OPCs, and it is unknown whether inhibiting RIPK1 activity directly affect OPCs, the central player of remyelination. Using TNFα induced RIPK1-dependent necroptosis in Jurkat FADD−/− cells as a cell death assay, we screened from 2112 FDA-approved drugs and the drug candidates of new RIPK1 inhibitors selected by ourselves, and identified ZJU-37, a small molecule modified by introducing an amide bond to Nec-1s, is a new RIPK1 kinase inhibitor with higher potency than Nec-1s which has the best reported potency. We unveil in addition to protecting myelin from demyelination and axons from degeneration, ZJU-37 exhibits a new role on promoting proliferation of OPCs and enhancing remyelination by inhibiting RIPK1 kinase activity with higher potency than Nec-1s. Mechanistically, ZJU-37 promotes proliferation of OPCs by enhancing the transcription of platelet derived growth factor receptor alpha via NF-κB pathway. This work identifies ZJU-37 as a new drug candidate which enhances remyelination by promoting proliferation of OPCs, paving the way for a potential drug to enhance myelin repair.

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RIPK1 activation mediates neuroinflammation and disease progression in multiple sclerosis

Abstract: Highlights d Insoluble RIPK1 activity and expression are elevated in progressive forms of MS d RIPK1 activation in microglia and astrocytes drives an inflammatory gene signature d Therapeutic RIPK1 inhibition attenuates symptoms in a progressive mouse model of MS

Cited by 78 publications

References 70 publications

The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells

The SARS-CoV-2 main protease Mpro causes microvascular brain pathology by cleaving NEMO in brain endothelial cells

Multiple Sclerosis and SARS-CoV-2: Has the Interplay Started?

Inhibition of RIPK1 by ZJU-37 promotes oligodendrocyte progenitor proliferation and remyelination via NF-κB pathway

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