Fatal cytokine release syndrome by an aberrant FLIP/STAT3 axis

Musiu, C.; Caligola, S.; Fiore, A.; Lamolinara, A.; Frusteri, C.; Del Pizzo, F. D.; De Sanctis, F.; Cane', S.; Adamo, A.; Hofer, F.; Barouni, R. M.; Grilli, A.; Zilio, S.; Serafini, P.; Tacconelli, E.; Donadello, K.; Gottin, L.; Polati, E.; Girelli, D.; Polidoro, I.; Iezzi, P. A.; Angelucci, D.; Capece, A.; Chen, Y.; Shi, Z.-L.; Murray, P. J.; Chilosi, M.; Amit, I.; Bicciato, S.; Iezzi, M.; Bronte, V.; Ugel, S.

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 homologue 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.