MAFB Determines Human Macrophage Anti- Inflammatory Polarization: Relevance for the Pathogenic Mechanisms Operating in Multicentric Carpotarsal Osteolysis

Macrophage phenotypic and functional heterogeneity derives from tissue-specific transcriptional signatures shaped by the local microenvironment. Most studies addressing the molecular basis formacrophage heterogeneity have focused onmurine cells, whereas the factors controlling the functional specialization of human macrophages are less known. M-CSF drives the generation of humanmonocyte-derived macrophageswith a potent anti-inflammatory activity upon stimulation. We now report that knockdown ofMAFBimpairs the acquisition of the anti-inflammatory profile of human macrophages, identify the MAFB-dependent gene signature in human macrophages and illustrate the coexpression of MAFB and MAFB-target genes in CD163(+) tissue-resident and tumor-associated macrophages. The contribution of MAFB to the homeostatic/anti-inflammatory macrophage profile is further supported by the skewed polarization of monocyte-derived macrophages from multicentric carpotarsal osteolysis (Online Mendelian Inheritance in Man # 166300), a pathology caused by mutations in the MAFB gene. Our results demonstrate that MAFB critically determines the acquisition of the antiinflammatory transcriptional and functional profiles of human macrophages.