The assembly of neutrophil inflammasomes during COVID-19 is mediated by type I interferons.

The severity of COVID-19 is linked to excessive inflammation. Neutrophils represent a critical arm of the innate immune response and are major mediators of inflammation, but their role in COVID-19 pathophysiology remains poorly understood. We conducted transcriptomic profiling of neutrophils obtained from patients with mild and severe COVID-19, as well as from SARS-CoV-2 infected mice, in comparison to non-infected healthy controls. In addition, we investigated the inflammasome formation potential in neutrophils from patients and mice upon SARS-CoV-2 infection. Transcriptomic analysis of polymorphonuclear cells (PMNs), consisting mainly of mature neutrophils, revealed a striking type I interferon (IFN-I) gene signature in severe COVID-19 patients, contrasting with mild COVID-19 and healthy controls. Notably, low-density granulocytes (LDGs) from severe COVID-19 patients exhibited an immature neutrophil phenotype and lacked this IFN-I signature. Moreover, PMNs from severe COVID-19 patients showed heightened nigericin-induced caspase1 activation, but reduced responsiveness to exogenous inflammasome priming. Furthermore, IFN-I emerged as a priming stimulus for neutrophil inflammasomes. These findings suggest a potential role for neutrophil inflammasomes in driving inflammation during severe COVID-19. Altogether, these findings open promising avenues for targeted therapeutic interventions to mitigate the pathological processes associated with the disease. Author summary: COVID-19, caused by the SARS-CoV-2, ranges from mild "flu"-like symptoms to severe respiratory distress or even death. Neutrophils are important cells of our immune system which are strongly involved in inflammatory responses, including those occurring in COVID-19. However, despite extensive research, the precise contribution of neutrophils to the pathogenesis of COVID-19 remains elusive, and further clarification on their role is still needed. In this study, we isolated neutrophils from COVID-19 patients and healthy controls to analyze changes in their gene expression profile and inflammatory functions. These analyses revealed a distinct type I interferon (IFN-I) gene signature expressed by mature, but not immature, neutrophils from severe COVID-19 patients, which was absent in mild cases and healthy controls. Additionally, neutrophils from severe COVID-19 showed signs of increased inflammasome activation, a protein complex that contributes to inflammation by releasing inflammatory cytokines. Notably, IFN-I alone was able to promote neutrophil inflammasome formation in vitro suggesting a direct link between IFN-I response and inflammasome formation during COVID-19. Furthermore, increased neutrophil inflammasome activity was detected also in a mouse model of COVID-19. These findings suggest a potential role for neutrophils in driving excessive inflammation during severe COVID-19, and a role for IFN-I in priming the assembly of inflammasomes in these cells. [ABSTRACT FROM AUTHOR]