Integrated Evidence for Lysosomal Dysfunction-Mediated Iron Dysregulation induced by PM2.5 Exposure

The precise manifestations of iron (Fe) imbalance, especially Fe2+ deficiency, are critical for addressing the health effects of ambient fine particulate matter (PM2.5) on human health. This study integrates epidemiological and in vitro and in vivo evidence to elucidate the role of Fe homeostasis in the effects of PM2.5 exposure on lung injury. Serum was collected from 35 women from Hebei Province, North China, and their residential PM2.5 concentrations were monitored from January 2015 to January 2016. We found that the ferritin light chain (FTL) in serum was positively associated with the PM2.5 concentration, suggesting that PM2.5 disrupts Fe homeostasis in the human body. Intratracheal instillation of naphthalene-1,4-dione-coated black carbon (1,4-NQ-BC), a PM2.5 analogue, increased FTL, but impaired the autophagy flux in rat lungs. 1,4-NQ-BC reduced Fe2+, but increased total Fe in RAW264.7 cells, when there was unimpaired Fe transportation through cell membranes. Likewise, 1,4-NQ-BC activated autophagy, but impaired lysosomal function, consequently inhibiting the autophagic flux in RAW264.7 cells. The role of lysosome dysfunction in PM-induced Fe2+ deficiency was revealed for the first time, via overexpression of transcription factor EB in a RAW264.7 cell model. We concluded that lysosomal damage-evoked Fe2+ deficiency provided sensitive biomarkers and potential therapeutic targets in pulmonary injury associated with ambient PM2.5 exposure.