MAFB and MAF cooperatively orchestrate human anti-inflammatory macrophage identity via autocrine Interleukin-10

Macrophage lineage identity is governed by intricate transcriptional networks. Although the large MAF basic region-leucine zipper (bZIP) transcription factors MAFB and MAF are critical regulators of anti-inflammatory programs, their molecular coordination and non-redundant contributions within human macrophages remain poorly defined. Here, utilizing integrated proteomic, transcriptomic, and epigenomic profiling, we demonstrate that endogenous MAFB and MAF physically associate to form a stable heterodimeric complex on chromatin in human M-CSF-dependent monocyte-derived macrophages (M-Mac). Genome-wide CUT&Tag mapping reveals a hierarchical epigenomic architecture in which MAFB acts as the primary global anchor of M-Mac identity, whereas MAF provides localized transcriptional tuning. Mechanistically, both factors directly bind the IL10 locus, but functional IL-10 expression is primarily driven by MAFB. Neutralizing antibody assays reveal that endogenously produced IL-10 establishes an obligate autocrine feedback loop mandatory for both the initial acquisition and the maintenance of the M-Mac anti-inflammatory profile. Functionally, MAFB and MAF exert non-redundant control over core macrophage effectors: MAFB dictates apoptotic cell efferocytosis amd T cell activation, whereas MAF modulates phagocytosis, and acts as a brake suppressing acute pro-inflammatory cytokine/chemokine hyper-induction. Together, these findings establish a comprehensive molecular blueprint of how MAFB and MAF cooperatively fine-tune human monocyte-derived macrophage identity and functional plasticity.