Efferocytosis of SARS-CoV-2-infected dying cells impairs macrophage anti-inflammatory programming and continual clearance of apoptotic cells

dos-Santos, D.; Salina, A. C. G.; Rodrigues, T. S.; Rocha, M. F.; Freitas-Filho, E. G.; Alzamora-Terrel, D. L.; de Lima, M. H. F.; Nascimento, D. B. C.; Castro, I.; Silva, C. M.; Toller-Kawahisa, J. E.; Becerra, A.; Oliveira, S.; Caetite, D. B.; Almeida, L.; Ishimoto, A. Y.; Lima, T. M.; Martins, R. B.; Veras, F.; do Amaral, N. B.; Giannini, M. C.; Bonjorno, L. P.; Lopes, M. I. F.; Benatti, M. N.; Batah, S. S.; Santana, R. C.; Vilar, F. C.; Martins, M. A.; Assad, R. L.; de Almeida, S. C. L.; de Oliveira, F. R.; Arruda Neto, E.; Cunha, T. M.; Alves-Filho, J. C.; Cunha, F. Q.; Fabro, A. T.; Naka,

COVID-19 is a disease of dysfunctional immune responses, but the mechanisms triggering immunopathogenesis are not established. The functional plasticity of macrophages allows this cell type to promote pathogen elimination and inflammation or suppress inflammation and promote tissue remodeling and injury repair. During an infection, the clearance of dead and dying cells, a process named efferocytosis, can modulate the interplay between these contrasting functions. Here, we show that engulfment of SARS-CoV2-infected apoptotic cells (AC) exacerbates inflammatory cytokine production, inhibits the expression of efferocytic receptors, and impairs continual efferocytosis by macrophages. We also provide evidence that monocytes from severe COVID-19 patients express reduced levels of efferocytic receptors and fail to uptake AC. Our findings reveal that dysfunctional efferocytosis of SARS-CoV-2-infected cell corpses suppress macrophage anti-inflammation and efficient tissue repair programs and provide mechanistic insights for the pathogenesis of the hyperinflammation and extensive tissue damage associated with COVID-19.