biostudies-literatureTsukalov IMinistry of Economy and Competitiveness | Instituto de Salud Carlos III (Institute of Health Carlos III)Comunidad de MadridMinistry of Economy and Competitiveness | Instituto de Salud Carlos IIIMinisterio de Economía y Competitividad (Ministry of Economy and Competitiveness)Ministerio de Economía y CompetitividadMinistry of Economy and Competitiveness | Agencia Estatal de InvestigaciónMinistry of Economy and Competitiveness | Agencia Estatal de Investigación (Spanish Agencia Estatal de Investigación)2100https://www.ebi.ac.uk/biostudies/studies/S-EPMC10920883biostudies-literatureUnknown15(1)Increased recruitment of transitional and non-classical monocytes in the lung during SARS-CoV-2 infection is associated with COVID-19 severity. However, whether specific innate sensors mediate the activation or differentiation of monocytes in response to different SARS-CoV-2 proteins remain poorly characterized. Here, we show that SARS-CoV-2 Spike 1 but not nucleoprotein induce differentiation of monocytes into transitional or non-classical subsets from both peripheral blood and COVID-19 bronchoalveolar lavage samples in a NFκB-dependent manner, but this process does not require inflammasome activation. However, NLRP3 and NLRC4 differentially regulated CD86 expression in monocytes in response to Spike 1 and Nucleoprotein, respectively. Moreover, monocytes exposed to Spike 1 induce significantly higher proportions of Th1 and Th17 CD4 + T cells. In contrast, monocytes exposed to Nucleoprotein reduce the degranulation of CD8 + T cells from severe COVID-19 patients. Our study provides insights in the differential impact of innate sensors in regulating monocytes in response to different SARS-CoV-2 proteins, which might be useful to better understand COVID-19 immunopathology and identify therapeutic targets.Nature communicationsNFκB and NLRP3/NLRC4 inflammasomes regulate differentiation, activation and functional properties of monocytes in response to distinct SARS-CoV-2 proteins.PMC10920883INMUNOVACTER REACT-EUCIBERINFECCPID-2020-120412RB-I00Inmunovacter REACT-UEPID2021-127899OB-I00CIBERCVPDC2021-121719-I00Esparcia LGonzalez Alvaro Ide Los Santos ICalvet-Mirabent MAlfranca AIturricastillo GMartinez-Fleta PMarcos-Jimenez ASanchez-Cerrillo IAncochea JScagnetti CSanchez-Madrid FGenesca MMartin-Cofreces NBuzon MJRajas OTsukalov ICalzada MJPopova OMunoz-Calleja CDelgado-Arevalo CMartin-Gayo EAvalos EPalacios-Calvo JfalseNFκB and NLRP3/NLRC4 inflammasomes regulate differentiation, activation and functional properties of monocytes in response to distinct SARS-CoV-2 proteins.Increased recruitment of transitional and non-classical monocytes in the lung during SARS-CoV-2 infection is associated with COVID-19 severity. However, whether specific innate sensors mediate the activation or differentiation of monocytes in response to different SARS-CoV-2 proteins remain poorly characterized. Here, we show that SARS-CoV-2 Spike 1 but not nucleoprotein induce differentiation of monocytes into transitional or non-classical subsets from both peripheral blood and COVID-19 bronchoalveolar lavage samples in a NFκB-dependent manner, but this process does not require inflammasome activation. However, NLRP3 and NLRC4 differentially regulated CD86 expression in monocytes in response to Spike 1 and Nucleoprotein, respectively. Moreover, monocytes exposed to Spike 1 induce significantly higher proportions of Th1 and Th17 CD4 + T cells. In contrast, monocytes exposed to Nucleoprotein reduce the degranulation of CD8 + T cells from severe COVID-19 patients. Our study provides insights in the differential impact of innate sensors in regulating monocytes in response to different SARS-CoV-2 proteins, which might be useful to better understand COVID-19 immunopathology and identify therapeutic targets.2024-01-01T00:00:00Z2024 Mar2026-06-27T03:17:14.639Z2026-06-27T03:06:48.315ZS-EPMC109208833845394910.1038/s41467-024-46322-8