Early 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.
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