The effect of PM2.5 exposure on lung inflammation and mitochondrial dysfunction using a macrophage-alveolar organoid co-culture system

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Background: Accumulation of Particulate matter (PM) as small as ≤2.5 microns (PM2.5) has adverse effects on human health, particularly in respiratory diseases. However, the molecular mechanisms by which PM2.5 exerts these effects are not fully understood. This study investigated that the effects of PM2.5 on THP-1-derived macrophage cells and alveolar organoids by micro-trans-well co-cultures system and explored the potential mechanisms. Methods: Using bioinformatic analysis, we found that differentially expressed genes (DEGs) to changes in the RNA-sequencing. Moreover, we have functionally validated cell-cell interaction using a co-culture system. Results: We observed significant up/down-regulated genes in the diesel-derived PM2.5 exposed macrophages and alveolar organoids compared with those in the control group. Among the differentially expressed genes (DEGs) in the macrophages, we detected 93 up-regulated genes and 171 down-regulated genes. Using bioinformatic analysis, we found that that down-regulated phagosome and HIF-1 link exposure to PM2.5. As a result, exposure to PM 2.5 in the co-culture system may cause mitochondrial dysfunction and activate FUNDC and p62, which are related to mitophagy, as demonstrated by relative mRNA and protein expressions. The excess ROS induced by PM2.5 impaired mitophagy, which is mitochondrial homeostasis. Conclusion: Our findings provide some insights into mechanisms' role in respiratory patients' response to air pollutants, which may help the new strategies to attenuate air pollution-associated respiratory diseases.

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