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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.<\/jats:p>","DOI":"10.1371\/journal.ppat.1012368","type":"journal-article","created":{"date-parts":[[2024,8,22]],"date-time":"2024-08-22T13:28:43Z","timestamp":1724333323000},"page":"e1012368","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["The assembly of neutrophil inflammasomes during COVID-19 is mediated by type I interferons"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9437-1010","authenticated-orcid":true,"given":"Luz E.","family":"Cabrera","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suvi T.","family":"Jokiranta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanna","family":"M\u00e4ki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simo","family":"Miettinen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ravi","family":"Kant","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauri","family":"Kareinen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tarja","family":"Sironen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jukka-Pekka","family":"Pietil\u00e4","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anu","family":"Kantele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eliisa","family":"Kek\u00e4l\u00e4inen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hanna","family":"Lindgren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pirkko","family":"Mattila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anja","family":"Kipar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olli","family":"Vapalahti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomas","family":"Strandin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,8,22]]},"reference":[{"key":"ppat.1012368.ref001","article-title":"Multi-omic profiling reveals widespread dysregulation of innate immunity and hematopoiesis in COVID-19.","volume":"218","author":"AJ Wilk","year":"2021","journal-title":"Journal of Experimental Medicine."},{"key":"ppat.1012368.ref002","doi-asserted-by":"crossref","first-page":"1036","DOI":"10.1016\/j.cell.2020.04.026","article-title":"Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19","volume":"181","author":"D Blanco-Melo","year":"2020","journal-title":"Cell"},{"key":"ppat.1012368.ref003","first-page":"718","article-title":"Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients","volume":"369","author":"J Hadjadj","year":"2020","journal-title":"Science (1979)."},{"key":"ppat.1012368.ref004","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1038\/s41586-022-04421-w","article-title":"The cGAS\u2013STING pathway drives type I IFN immunopathology in COVID-19","volume":"603","author":"J Di Domizio","year":"2022","journal-title":"Nature"},{"key":"ppat.1012368.ref005","article-title":"Targeting potential drivers of COVID-19: Neutrophil extracellular traps","author":"BJ Barnes","year":"2020","journal-title":"Journal of Experimental Medicine. 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