Fatal cytokine release syndrome by an aberrant FLIP/STAT3 axis

Chiara Musiu, Simone Caligola, Alessandra Fiore, Alessia Lamolinara, Cristina Frusteri, Francesco Domenico Del Pizzo, Francesco De Sanctis, Stefania Canè, Annalisa Adamo, Francesca Hofer, Roza Maria Barouni, Andrea Grilli, Serena Zilio, Paolo Serafini, Evelina Tacconelli, Katia Donadello, Leonardo Gottin, Enrico Polati, Domenico Girelli, Ildo PolidoroPiera Amelia Iezzi, Domenico Angelucci, Andrea Capece, Ying Chen, Zheng Li Shi, Peter J. Murray, Marco Chilosi, Ido Amit, Silvio Bicciato, Manuela Iezzi, Vincenzo Bronte, Stefano Ugel

Research output: Contribution to journalArticlepeer-review

2 Scopus citations


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.

Original languageEnglish (US)
JournalCell Death and Differentiation
StateAccepted/In press - 2021

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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