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


  • D. Dörr
  • B. Obermayer
  • J.M. Weiner
  • K. Zimmermann
  • C. Anania
  • L.K. Wagner
  • E.M. Lyras
  • V. Sapozhnikova
  • D. Lara-Astiaso
  • F. Prósper
  • R. Lang
  • D.G. Lupiáñez
  • D. Beule
  • U.E. Höpken
  • A. Leutz
  • A. Mildner


  • Science Immunology


  • Sci Immunol 7 (75): eabj0140


  • 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.