C/EBPβ regulates lipid metabolism and Pparg isoform 2 expression in alveolar macrophages

Pulmonary alveolar proteinosis (PAP) is a syndrome characterized by accumulation of surfactant lipoproteins within the lung alveoli. Alveolar macrophages (AMs) are crucial for surfactant clearance and their differentiation depends on colony-stimulating factor 2 (CSF2) and the establishment of an AM-characteristic gene regulatory network. Here we report that the transcription factor C/EBPβ is essential for the development of the AM identity, as demonstrated by transcriptome and chromatin accessibility analysis. Furthermore, C/EBPβ-deficient AMs showed severe defects in proliferation, phagocytosis and lipid metabolism, collectively resulting in a PAP-like syndrome. Mechanistically, the long C/EBPβ protein variants LAP* and LAP together with CSF2 signaling induced expression of Pparg isoform2, but not isoform1, a molecular regulation that was also observed in other CSF2-primed macrophages. These results uncover C/EBPβ as a key regulator of AM cell fate and as the missing link between CSF2 and Pparg isoform 2 expression, thereby regulating lipid turnover in AMs. Comparison of transcriptome and chromatin assesibility of different mouse Cebpb mutant alveolar macrophages against respective controls