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Fatal cytokine release syndrome by an aberrant FLIP/STAT3 axis
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 d...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435761/ https://www.ncbi.nlm.nih.gov/pubmed/34518653 http://dx.doi.org/10.1038/s41418-021-00866-0 |
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author | Musiu, Chiara Caligola, Simone Fiore, Alessandra Lamolinara, Alessia Frusteri, Cristina Del Pizzo, Francesco Domenico De Sanctis, Francesco Canè, Stefania Adamo, Annalisa Hofer, Francesca Barouni, Roza Maria Grilli, Andrea Zilio, Serena Serafini, Paolo Tacconelli, Evelina Donadello, Katia Gottin, Leonardo Polati, Enrico Girelli, Domenico Polidoro, Ildo Iezzi, Piera Amelia Angelucci, Domenico Capece, Andrea Chen, Ying Shi, Zheng-Li Murray, Peter J. Chilosi, Marco Amit, Ido Bicciato, Silvio Iezzi, Manuela Bronte, Vincenzo Ugel, Stefano |
author_facet | Musiu, Chiara Caligola, Simone Fiore, Alessandra Lamolinara, Alessia Frusteri, Cristina Del Pizzo, Francesco Domenico De Sanctis, Francesco Canè, Stefania Adamo, Annalisa Hofer, Francesca Barouni, Roza Maria Grilli, Andrea Zilio, Serena Serafini, Paolo Tacconelli, Evelina Donadello, Katia Gottin, Leonardo Polati, Enrico Girelli, Domenico Polidoro, Ildo Iezzi, Piera Amelia Angelucci, Domenico Capece, Andrea Chen, Ying Shi, Zheng-Li Murray, Peter J. Chilosi, Marco Amit, Ido Bicciato, Silvio Iezzi, Manuela Bronte, Vincenzo Ugel, Stefano |
author_sort | Musiu, Chiara |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8435761 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-84357612021-09-13 Fatal cytokine release syndrome by an aberrant FLIP/STAT3 axis Musiu, Chiara Caligola, Simone Fiore, Alessandra Lamolinara, Alessia Frusteri, Cristina Del Pizzo, Francesco Domenico De Sanctis, Francesco Canè, Stefania Adamo, Annalisa Hofer, Francesca Barouni, Roza Maria Grilli, Andrea Zilio, Serena Serafini, Paolo Tacconelli, Evelina Donadello, Katia Gottin, Leonardo Polati, Enrico Girelli, Domenico Polidoro, Ildo Iezzi, Piera Amelia Angelucci, Domenico Capece, Andrea Chen, Ying Shi, Zheng-Li Murray, Peter J. Chilosi, Marco Amit, Ido Bicciato, Silvio Iezzi, Manuela Bronte, Vincenzo Ugel, Stefano Cell Death Differ Article 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. Nature Publishing Group UK 2021-09-13 2022-02 /pmc/articles/PMC8435761/ /pubmed/34518653 http://dx.doi.org/10.1038/s41418-021-00866-0 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Article Musiu, Chiara Caligola, Simone Fiore, Alessandra Lamolinara, Alessia Frusteri, Cristina Del Pizzo, Francesco Domenico De Sanctis, Francesco Canè, Stefania Adamo, Annalisa Hofer, Francesca Barouni, Roza Maria Grilli, Andrea Zilio, Serena Serafini, Paolo Tacconelli, Evelina Donadello, Katia Gottin, Leonardo Polati, Enrico Girelli, Domenico Polidoro, Ildo Iezzi, Piera Amelia Angelucci, Domenico Capece, Andrea Chen, Ying Shi, Zheng-Li Murray, Peter J. Chilosi, Marco Amit, Ido Bicciato, Silvio Iezzi, Manuela Bronte, Vincenzo Ugel, Stefano Fatal cytokine release syndrome by an aberrant FLIP/STAT3 axis |
title | Fatal cytokine release syndrome by an aberrant FLIP/STAT3 axis |
title_full | Fatal cytokine release syndrome by an aberrant FLIP/STAT3 axis |
title_fullStr | Fatal cytokine release syndrome by an aberrant FLIP/STAT3 axis |
title_full_unstemmed | Fatal cytokine release syndrome by an aberrant FLIP/STAT3 axis |
title_short | Fatal cytokine release syndrome by an aberrant FLIP/STAT3 axis |
title_sort | fatal cytokine release syndrome by an aberrant flip/stat3 axis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435761/ https://www.ncbi.nlm.nih.gov/pubmed/34518653 http://dx.doi.org/10.1038/s41418-021-00866-0 |
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