C29-16 Mafb Governs the Profibrotic Program of Monocyte-derived Macrophages and Drives Lung Fibrosis

Abstract Rationale During lung injury repair, circulating monocytes are recruited to the lung, where they differentiate into macrophages known as monocyte-derived macrophages (Mo-Ms). Although Mo-Ms are recognized as pivotal drivers of pulmonary fibrosis, the molecular mechanisms that govern their pathogenic phenotype and fate remain poorly defined. Moreover, how modulating these pathways influences disease progression and whether Mo-M-specific mechanisms can be therapeutically targeted are largely unexplored. Methods Alveolar macrophages were isolated by flow cytometry and cell sorting. A mouse model with Mo-AM-specific deletion of MafB was employed to study the role of MafB in lung fibrosis. Public and in-house single-cell RNA sequencing (scRNA-seq) datasets were analyzed to assess MafB expression across human and mouse lung cell populations. Results We identified MafB, a member of the large MAF transcription factor family, as one of the most highly upregulated transcription factors in alveolar macrophages from fibrotic mouse lungs. MafB expression decreased progressively as classical monocytes differentiated into Mo-Ms and subsequently into tissue-resident macrophages (TR-Ms). Genetic ablation of MafB in Mo-Ms did not affect their differentiation but markedly reduced their expression of profibrotic mediators. Correspondingly, MafB+ macrophages were enriched within fibrotic niches containing activated fibroblasts and aberrant transitional-state epithelial cells. These fibroblast and epithelial populations were significantly reduced in mice lacking MafB in Mo-Ms. Strikingly, deletion of MafB-either before or one week after bleomycin administration-conferred strong protection against lung fibrosis. Transcriptomic analysis revealed that expression of C1qa/b/c, but not other complement components, was entirely dependent on MafB. Deletion of C1qa in Mo-Ms phenocopied the antifibrotic effect observed with MafB deficiency. Importantly, in patients with idiopathic pulmonary fibrosis (IPF), lung macrophages exhibited elevated MafB expression, and MafBʰigh macrophages displayed an enhanced profibrotic transcriptional signature. Conclusions Our findings identify MafB as a key transcriptional regulator sustaining the profibrotic activity of monocyte-derived alveolar macrophages. Targeting MafB and its downstream effectors in Mo-Ms represents a promising therapeutic strategy to mitigate pulmonary fibrosis by limiting the excessive profibrotic responses of these macrophages. This abstract is funded by: NIH