Macrophage phagocytosis of SARS-CoV-2-infected cells mediates potent plasmacytoid dendritic cell activation

Abstract

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.

Microplastics dysregulate innate immunity in the SARS-CoV-2 infected lung

“…Significantly reduced numbers of pDC were identified in the BA.5+MP group by cellular deconvolution using NanoString expression matrices ( Figure 3 , pDC, Supplementary Table 5 ), consistent with the reduction in M1 macrophages ( 85 ). As might be expected, viral load and pDC abundance showed positive correlations, with pDC abundance lower for the BA.5+MP group across all viral loads ( Figure 3B ).…”

“…MPs were recently reported to inhibit phagocytosis of apoptotic cells (known as efferocytosis) ( 42 ), and a top IPA Diseases and Functions annotation was ‘Phagocytosis’, with a high negative z score ( Figure 3A , Phagocytosis; Supplementary Table 5 ). During infection, macrophages phagocytose SARS-CoV-2-infected cells and are thereby activated, and in turn mediate strong activation of plasmacytoid dendritic cells (pDC) ( 85 ). The reduced phagocytosis is thus consistent with a reduction in activated M1 macrophages identified via a series of annotations ( Figure 3 , M1 macrophages); specifically (i) reduced abundance of polyinosinic:polycytidylic acid (pIC) stimulated macrophages (a stimulus that mimics viral double stranded RNA), (ii) a series of IPA Canonical pathways and Diseases and Functions macrophage annotations with negative z scores, and (iii) GSEAs with negative NES and q<0.05 using M1 macrophage gene sets from Xue at al., 2014 ( 65 ) ( Supplementary Table 5 ).…”

“…Specifically, the clearly depressed phagocytosis signatures, the identification of multiple annotations associated with modulation of macrophage responses (with macrophages the key mediators of efferocytosis), and the overall lack of detectable changes to adaptive immune responses, might be viewed as consistent with a role for dysregulated phagocytosis/efferocytosis ( 115 , 116 ). Reduced phagocytosis of SARS-CoV-2 infected cells at 2 dpi might reduce M1 macrophage activation, subsequent pDC activation ( 85 ), and the ensuing cytokine responses ( 86 , 136 ). Less phagocytosis at the peak of infection might also lead to more secondary necrosis and/or necroptosis of SARS-CoV-2 infected cells, thereby promoting inflammation at 6 dpi ( 137 , 138 ).…”

SARS-CoV2 infection in whole lung primarily targets macrophages that display subset-specific responses

“…In the context of the current literature, these results align with previous reports but con ict with others. Indeed, several studies showed that exposure of monocytes/macrophages to SARS-CoV-2 triggered the synthesis of in ammatory cytokines, as we found [63][64][65][66][67][68] , whereas others reported that it did not [69][70][71][72][73] . Most of the studies cited above implicated macrophages differentiated in vitro from monocytes, and may not display the same functional properties as monocytes and macrophages imprinted by the lung tissue.…”

SARS-CoV-2 Spike Protein Stimulates Macropinocytosis in Murine and Human Macrophages via PKC-NADPH Oxidase Signaling

“…Nevertheless, many macrophages have shown to be positive for SARS-CoV-2 RNA or protein in vivo [44,45], suggesting an ACE2-independent mechanism of viral entry into macrophages. Recent studies have shown that SARS-CoV-2 can infect host cells via clathrin-mediated endocytosis [46], caveolae-dependent endocytosis [47], phagocytosis [48], and macropinocytosis [12] to initiate an inflammatory cascade.…”