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

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.