Our results demonstrate the involvement of MAFB in the expression of the genes that characterize pathogenic macrophage clusters in severe COVID-19 and reveal that MAFB expression is potentiated in infected M-MØ and GM-MØ, where it controls the expression of profibrotic factors (IL-10, CCL2, CCL18, CXCL12, CXCL13, SPP1) and neutrophil-attracting chemokines like CXCL2 and CXCL5, some of which act as potentially useful prognostic biomarkers for COVID-19 severity. Here, CXCL12 is linked to COVID-19.