The Impact of Environmental Respiratory Hazards on Pulmonary Macrophages 2259898

Abstract Introduction Environmental respiratory hazards (ERH) are associated with pulmonary disease and lung cancer. Yet, the mechanisms by which ERH disrupt lung immunity, and pulmonary macrophages (pMac) in particular, are largely unknown. Methods FVB mice were exposed to aerosolized ERHs for 1wk or 4wks and pMacs were assessed by ATACseq and RNAseq. Primary and Raw264.7 macrophage function was determined after co-culture with ERHs. Spatial transcriptomics (GeoMx) for pMac and epithelial gene expression was performed on paired non-malignant lung tissue and lung tumors from patients (N = 28). Patient ERH exposure levels were constructed from 1-year prior to surgery using census tract-level daily PM2.5, ozone, and NO2 estimates from the EPA and confirmed with polarized light microscopy. Results Increasing duration of ERH exposures in mice resulted in a durable epigenetic shift in pMacs from pro-resolution to tissue remodeling. Functionally, ERHs inhibited wound healing and phagocytosis which could be reverted by enhancing mitochondria with the AMPK agonist AICAR. In ERHHigh patients, pMacs in lung tissue expressed gene profiles of complement and coagulation driven by KLF4, PPARγ, and RUNX1. By contrast, pMacs in ERHLow lung drove chemokine signaling via RELA/RELB, STAT4, and IRF8. Notably, epithelial cells surrounding pMacs expressed divergent transcriptional profiles between ERHHigh and ERHLow patients. Tumor-associated macrophages (TAMs) from ERHHigh patients were transcriptionally poised for ECM remodeling and expressed KLF4 and RUNX2, whereas TAMs in ERHLow tumors were enriched for lipoprotein metabolism with RELA, IRF6, and SMAD4 expression. Conclusion ERH exposures result in epigenetic dysregulation in pMacs, inhibiting function, in part, through decreased bioenergetics. Clinically, ERHs were associated with distinct molecular pathways in pMacs which altered surrounding epithelium and may inform precision drug development and risk modeling in lung disease. Funding Source n/a Topic Categories Mucosal and Regional Immunology (MUC)