ABSTRACT
Excessive inflammation defines COVID-19 pathophysiology. Neutrophils represent a critical arm of the innate immune response and are major mediators of inflammation. We conducted transcriptomic profiling of polymorphonuclear cells (PMNs), consisting mainly of mature neutrophils, which revealed a pronounced type I interferon (IFN-I) gene signature in severe COVID-19, compared to mild COVID-19 and healthy controls. Notably, low-density granulocytes (LDGs) from severe COVID-19 did not exhibit this signature and displayed a distinct immature neutrophil phenotype. PMNs from severe COVID-19 patients showed heightened nigericin-induced caspase1 activation but reduced responsiveness to exogenous inflammasome priming. Interestingly, while mature neutrophils efficiently released IL-1? upon inflammasome activation, they were poor producers of IL-18. Furthermore, IFN-I emerged as a priming stimulus for neutrophil inflammasomes, which was confirmed in a COVID-19 mouse model. Overall, these findings underscore the crucial role of neutrophil inflammasomes in driving inflammation during severe COVID-19 and opens promising avenues for targeted therapeutic interventions to mitigate the pathological processes associated with the disease.