PBRM1 modulates alveolar macrophage homeostasis & oxidative stress response 9047

Abstract Description Alveolar macrophages (AMs) are indispensable in maintaining pulmonary homeostasis and proper host defense against respiratory diseases. This role is conferred through their distinct transcriptional profile and specialized functions (e.g. alveolar surfactant turnover, bacterial clearance, & secretion of anti-inflammatory cytokines). Like other types of tissue resident macrophages, AMs exhibit a unique gene signature downstream of tissue-specific signaling that drives their development and maintains their identity as resident AMs. Several transcription factors proven to be critical toward AM development and function are also involved in regulating the specialized metabolic profile of AMs (i.e. PPAR? & C/EBPβ). However, our knowledge of AMs’ transcriptional regulatory network remains largely incomplete. Here, we identified PBRM1, a core subunit of the ATP-dependent chromatin remodeling complex PBAF, as a regulator of lipid metabolism and the oxidative stress response in AMs. Myeloid-specific Pbrm1 deletion in mice reduces homeostatic AM numbers and dysregulates the NRF2 pathway, impacting cytoprotective enzymes involved in lipid metabolism and redox balance. Elevated levels of reactive oxygen species and lipid peroxidation are observed in Pbrm1-deficient AMs, both of which are hallmarks for a type of oxidative cell death known as ferroptosis. Altogether, we have found a role for PBRM1 in transcriptional regulatory networks required for tissue specific functions of AMs. Funding Sources Supported by NIH F31HL167460; Society of Research Fellows Travel Award: The Salk Institute of Biological Sciences; UC San Diego School of Biological Sciences Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)