Histone deacetylase 1 and 2 play essential roles in alveolar macrophage homeostasis

Alveolar macrophages (AMs) are the primary lung-resident macrophages that play a pivotal role in pathogen clearance and surfactant homeostasis. Although the molecular regulation of AM development at the transcriptional level has been more widely studied, the epigenetic mechanisms that maintain AM homeostasis remain incompletely understood. Here, we demonstrate that histone deacetylases HDAC1 and HDAC2 play essential roles in preserving AM integrity. Dual deletion of HDAC1 and HDAC2 resulted in severe defect in AM development, leading to pulmonary alveolar proteinosis (PAP) and increased susceptibility to influenza infection in mice. Mechanistically, HDAC1 and HDAC2 act through their deacetylase activity to suppress the expression of pro-apoptotic protein Bim, thereby enhancing cell survival. Furthermore, HDAC1 and HDAC2 form a functional complex with the histone demethylase LSD1 (KDM1A) to co-regulate a transcriptional program governing AM differentiation. Our findings identify HDAC1 and HDAC2 as central epigenetic regulators essential for alveolar macrophage homeostasis.