Macrophage handling of particulate-laden cell corpses disrupts immunometabolism

About This Grant

PROJECT SUMMARY Bioaccumulation of particulate matter (PM) in the lungs is a key feature driving pulmonary disease development in the modern world, with 4.2 million deaths per year reported by the World Health Organization from ambient air exposure alone. Alveolar macrophages (AM) are professional phagocytes that comprise 95% of the leukocyte population in the alveoli, critical to maintaining systemic health and protection from environmental exposures by clearing pathogens, foreign particulates, and cell corpses from the alveolar space. However, the fate of non- degradable PM contained within macrophages (MΦ) following cell death is unknown. Previous work from our group shows that cell corpses transfer their endogenous metabolites to AM upon clearance, triggering anti- inflammatory metabolic and immune reprogramming in the engulfing AM. We hypothesize that any non- degradable PM contained within a cell corpse will also be transferred to the engulfing MΦ, and that the presence of PM will perturb MΦ immunometabolic reprogramming to instead promote chronic inflammation. We further hypothesize that the level of perturbation will differ between apoptotic versus necrotic cell death, with elevated disruption following engulfment of PM-exposed necrotic cells (NC). Using in vitro and in vivo systems, we will first expand upon our preliminary experiments investigating the characteristics of PM transfer from cell corpses to live MΦ, examining PM2.5 and amorphous silica. Preliminary studies indicate that the type of cell death impacts the way PM is transferred. Using a cytoskeletal inhibitor screen, we identified two compounds effective at blocking corpse uptake, but not PM transfer from NC to live MΦ. These findings provide tools we can use to study this unique mode of transfer. We also found that PM transfer from cell corpses impacts MΦ transcriptional reprogramming in response to corpse engulfment. Preliminary examination of MΦ response to PM10-exposed apoptotic cells (AC) or NC identified an upregulation of proinflammatory and metal response genes in engulfing MΦ when engulfed corpses contained PM10. Examining PM2.5, we will extend these preliminary studies of MΦ reprogramming to investigate the impacts of PM2.5-laden corpse engulfment on MΦ cytokine production and metabolism. Finally, a novel bone marrow chimera model will be used to study the endogenous in vivo response of recruited AM engulfing PM2.5-laden versus naïve apoptotic resident AM corpses. The transcriptome and metabolome of recruited AM sorted by engulfment will be assessed to characterize how the presence of PM in cellular corpses alters AM immunometabolic programming following engulfment in vivo. This proposal will address gaps in knowledge regarding AM and inhaled particulates that will advance our understanding of how PM exposures promote the development of chronic lung inflammation and disease.