Integrated Evidence for Lysosomal Dysfunction-Mediated Iron Dysregulation induced by PM 2 . 5 Exposure

The precise manifestations of iron (Fe) imbalance, especially Fe 2+ deficiency, are critical for addressing the health effects of ambient fine particulate matter (PM 2 . 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 PM 2 . 5 exposure on lung injury. Serum was collected from 35 women from Hebei Province, North China, and their residential PM 2 . 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 PM 2 . 5 concentration, suggesting that PM 2 . 5 disrupts Fe homeostasis in the human body. Intratracheal instillation of naphthalene-1,4-dione-coated black carbon (1,4-NQ-BC), a PM 2 . 5 analogue, increased FTL, but impaired the autophagy flux in rat lungs. 1,4-NQ-BC reduced Fe 2+, 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 Fe 2+ 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 Fe 2+ deficiency provided sensitive biomarkers and potential therapeutic targets in pulmonary injury associated with ambient PM 2 . 5 exposure.