High levels of cytokines IL-1β and IL-18 correlate with COVID-19 severity in patients. In Nature, Sefik et al. show that SARS-CoV-2 infection of lung-resident macrophages drives disease pathology. When mice with a humanized immune system (MISTRG6-hACE2) were infected with a tagged (mNG) SARS-CoV-2 strain, lung macrophages were mNG+ and viral subgenomic RNA+, indicating that the virus replicates in these cells. Infection is dependent on ACE2 and antibody-mediated Fc-receptor uptake. ASC formation, as a readout of inflammasome activation, is detected in mNG+ lung macrophages and correlates with serum levels of inflammatory cytokines (IL-18 and IL-1RA) and markers of pyroptosis (GSDMD). Blocking viral entry or replication in lung macrophages reduces expression of IL-18, IL-1RA and CXCL10. NLRP3 inhibitors attenuate the production of IL-18, IL-1RA and GSDMD, reverse lung immune pathology and induce higher viral loads in the lung, which suggests that inflammasome activation restricts viral propagation at the cost of hyperinflammation in the lung.
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Visan, I. Inflammatory macrophages. Nat Immunol 23, 988 (2022). https://doi.org/10.1038/s41590-022-01261-8