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

Abstract

Macrophage phenotypic and functional heterogeneity derives from tissue-specific transcriptional signatures shaped by the local microenvironment. Most studies addressing the molecular basis for macrophage heterogeneity have focused on murine cells, whereas the factors controlling the functional specialization of human macrophages are less known. M-CSF drives the generation of human monocyte-derived macrophages with a potent anti-inflammatory activity upon stimulation. We now report that knockdown of MAFB impairs 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.

Palmitate Conditions Macrophages for Enhanced Responses toward Inflammatory Stimuli via JNK Activation

“…1B). The ability of palmitate to downregulate the expression of the M-MØ-specific antiinflammatory gene set prompted us to determine its effects on the expression of transcription factors that control macrophage polarization (AhR, MAFB, C/EBPb) (18,25,26,32,33). M-MØ exhibited higher levels of MAFB and AhR than GM-MØ, whereas the latter exhibit a higher content of C/EBPb (Fig.…”

“…Therefore, palmitate stimulates M-MØ to reduce the expression of their specific anti-inflammatory gene set and to gain cytokine and transcription factor profiles that resemble GM-MØ. The palmitateinduced downregulation of MAFB protein expression is especially significant given the involvement of MAFB in the acquisition of an anti-inflammatory profile by human macrophages (26).…”

Role of MafB in macrophages

“…YFP expression clearly distinguished macrophage and other cell lineages, including DCs [77]. in human tissue, MAFB is expressed in macrophages in the skin and colon and in melanoma tumors [11]. MAFB expression has also been observed in CD16-positive human monocyte-derived macrophages [26].…”

“…Furthermore, RXR homodimers are involved in osteoclast differentiation through regulation of the expression of MafB [50]. MafB is also upregulated by certain cytokine signals, including M-CSF, IL-10, IL-4, and IL-13, and downregulated by GM-CSF and LPS [11,12,17]. In humans, vitamin D3/Hox-A10 regulates MafB expression during the differentiation of CD34 + cells to monocytes [16].…”

Transcriptional regulatory mechanisms of fibrosis development in mouse lung tissue exposed to carbon nanotubes

“…Mafb was identified in a module associated with FCGR activation and phagocytosis (as mentioned above), which was altered also at late time points in the NM-401 and BLM networks. Mafb can enhance phagocytic activity of macrophages by stimulating Fcgr3 [40] and has a key role in the activation of anti-inflammatory profile of macrophages by inducing M1/M2 macrophage polarization, which is important for fibrosis development [41,42]. Macrophages produce numerous cytokines, chemokines, matrix metalloproteinases, and other inflammatory and ECM remodeling mediators.…”