C/EBPβ regulates lipid metabolism and <i>Pparg</i> isoform 2 expression in alveolar macrophages
Dorothea Dörr, Benedikt Obermayer, January Weiner, Karin Zimmermann, Chiara Anania, Lisa Katharina Wagner, Ekaterini Maria Lyras, Valeriia Sapozhnikova, David Lara‐Astiaso, Felipe Prósper, Roland Lang, Darío G. Lupiáñez, Dieter Beule, Uta E. Höpken, Achim Leutz, Alexander Mildner
Abstract
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), which regulates the establishment of an AM-characteristic gene regulatory network. Here, we report that the transcription factor CCAAT/enhancer binding protein β (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 the expression of Pparg isoform 2 but not Pparg isoform 1, a molecular regulatory mechanism that was also observed in other CSF2-primed macrophages. These results uncover C/EBPβ as a key regulator of AM cell fate and shed light on the molecular networks controlling lipid metabolism in macrophages.