Fatal cytokine release syndrome by an aberrant FLIP/STAT3 axis
Open Access
- 13 September 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Differentiation
- Vol. 29 (2), 420-438
- https://doi.org/10.1038/s41418-021-00866-0
Abstract
Inflammatory responses rapidly detect pathogen invasion and mount a regulated reaction. However, dysregulated anti-pathogen immune responses can provoke life-threatening inflammatory pathologies collectively known as cytokine release syndrome (CRS), exemplified by key clinical phenotypes unearthed during the SARS-CoV-2 pandemic. The underlying pathophysiology of CRS remains elusive. We found that FLIP, a protein that controls caspase-8 death pathways, was highly expressed in myeloid cells of COVID-19 lungs. FLIP controlled CRS by fueling a STAT3-dependent inflammatory program. Indeed, constitutive expression of a viral FLIP homolog in myeloid cells triggered a STAT3-linked, progressive, and fatal inflammatory syndrome in mice, characterized by elevated cytokine output, lymphopenia, lung injury, and multiple organ dysfunctions that mimicked human CRS. As STAT3-targeting approaches relieved inflammation, immune disorders, and organ failures in these mice, targeted intervention towards this pathway could suppress the lethal CRS inflammatory state.Funding Information
- Cancer Research Institute (CLIP 2020)
- Ministero dell'Istruzione, dell'Università e della Ricerca (B38D19000260006, B38D19000140006)
- Associazione Italiana per la Ricerca sul Cancro (23788, 21509)
- Fondazione Cassa di Risparmio di Verona Vicenza Belluno e Ancona (Enact)
- Fondazione TIM (Project: Immunovid) European Research Commission
- Ministero dell'Istruzione, dell'Università e della Ricerca
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