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

• Published in: PLoS pathogens Vol. 20; no. 8; p. e1012368
• Main Authors: Cabrera, Luz E., Jokiranta, Suvi T., Mäki, Sanna, Miettinen, Simo, Kant, Ravi, Kareinen, Lauri, Sironen, Tarja, Pietilä, Jukka-Pekka, Kantele, Anu, Kekäläinen, Eliisa, Lindgren, Hanna, Mattila, Pirkko, Kipar, Anja, Vapalahti, Olli, Strandin, Tomas
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 22.08.2024; Public Library of Science (PLoS)
• Subjects: Adult; Analysis; Animals; B cells; Biological response modifiers; Biology and Life Sciences; COVID-19 - immunology; Ethylenediaminetetraacetic acid; Female; Genes; Health aspects; Humans; Immune response; Immunity, Innate; Infection; Inflammasomes - immunology; Inflammasomes - metabolism; Inflammation; Interferon; Interferon Type I - immunology; Interferon Type I - metabolism; Male; Medical research; Medicine and Health Sciences; Medicine, Experimental; Mice; Mice, Inbred C57BL; Middle Aged; Neutrophils; Neutrophils - immunology; Neutrophils - metabolism; Research and analysis methods; SARS-CoV-2 - immunology; Finland
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1012368

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.