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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...

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Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
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
Descripción
Sumario: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.