1 p.-4 fig.MAF and MAFB are members of the “large MAF” transcription factor family that shape the transcriptome of antiinflammatory and pro-tumoral human macrophages. We have now determined the MAF- and MAFB-dependent gene profile of M-CSF-dependent monocyte-derived macrophages (M-MØ), and found that both factors exhibit overlapping transcriptional outcomes during monocyte-to-M-MØ differentiation, but differentially affect macrophage effector functions like production of monocyte-recruiting chemokines, T-cell activation and immunosuppression. Remarkably, MAFB was found to positively regulate the expression of the genesets that define the pathogenic monocyte-derived pulmonary macrophage subsets in COVID-19, as evidenced through siRNA-mediated silencing and analysis of MAFBoverexpressing M-MØ from a Multicentric Carpotarsal Osteolysis (MCTO) patient. MAFB silencing downregulated theexpression of genes coding for biomarkers of COVID-19 severity, and genome-wide mapping of MAFB-binding elements in M-MØ identified biomarkers of COVID-19 severity (CD163, IL10, HGF and CCL2) as direct MAFB targets. Further, and in
line with the GSK3b-dependent expression of MAFB, GSK3b inhibition in M-MØ significantly boosted the expression of genes that characterize pathogenic macrophage subsets in severe COVID-19, an effect that was primarily dependent on MAFB. In addition, we have demonstrated that a large number of MAFB-dependent genes, as well as GSK3b-dependent expression of MAFB genes were modulated by SARS-Cov-2 infection on human macrophages. Globally, our results demonstrate that the GSK3b-MAFB axis controls the transcriptome of pathogenic pulmonary macrophages in COVID-19,and positively regulates the expression of biomarkers for COVID-19 severity. Thus, macrophage re-programming through modulation of GSK3 -MAFB axis has potential therapeutic strategy for COVID-19 and other inflammatory diseases.This research work was also funded by the European Commission– NextGenerationEU (Regulation EU 2020/2094), through CSIC's Global Health Platform (PTI Salud Global).Peer reviewe
