Garcia Nicolas, ObdulioObdulioGarcia NicolasGodel, AurélieAurélieGodelZimmer, GertGertZimmerSummerfield, ArturArturSummerfield0000-0001-8292-46342024-10-252024-10-252023-07https://boris-portal.unibe.ch/handle/20.500.12422/167536Early and strong interferon type I (IFN-I) responses are usually associated with mild COVID-19 disease, whereas persistent or unregulated proinflammatory cytokine responses are associated with severe disease outcomes. Previous work suggested that monocyte-derived macrophages (MDMs) are resistant and unresponsive to SARS-CoV-2 infection. Here, we demonstrate that upon phagocytosis of SARS-CoV-2-infected cells, MDMs are activated and secrete IL-6 and TNF. Importantly, activated MDMs in turn mediate strong activation of plasmacytoid dendritic cells (pDCs), leading to the secretion of high levels of IFN-α and TNF. Furthermore, pDC activation promoted IL-6 production by MDMs. This kind of pDC activation was dependent on direct integrin-mediated cell‒cell contacts and involved stimulation of the TLR7 and STING signaling pathways. Overall, the present study describes a novel and potent pathway of pDC activation that is linked to the macrophage-mediated clearance of infected cells. These findings suggest that a high infection rate by SARS-CoV-2 may lead to exaggerated cytokine responses, which may contribute to tissue damage and severe disease.enInflammatory cytokines Interferon-α Monocyte-derived macrophages Plasmacytoid dendritic cell SARS-CoV-2COVID-19600 - Technology::630 - Agriculturearticle10.48350/1830443725394610.1038/s41423-023-01039-4