Mechanistic insights into carbon black-activated AKT/TMEM175 cascade impairing macrophage-epithelial cross-talk and airway epithelial proliferation

Abstract

Carbon black nanoparticles (CB) has been linked to respiratory epithelial damage, a precursor to various respiratory diseases. Although the mechanisms by which CB induce cellular damage are well understood, the initial molecular events driving this process remain poorly characterized. In this study, we aim to elucidate the cellular responses triggered by CB exposure, focusing on the molecular conformational changes, organelle damage, and the disruption of crosstalk between macrophages and airway epithelial cells. Specifically, upon the phagocytosis of CB by macrophages, a reduction in the acidic environment of intracellular lysosomes, accompanied by decreased extracellular levels of arginine and glutamate. This change triggers the inhibition of airway epithelial proliferation. Additional, we identified TMEM175 as the key molecular target through which CB diminishes lysosomal acidity. Molecular dynamics simulations revealed that the π-π interactions between CB and AKT serve as the initiating event, leading to the inhibition of TMEM175 activation. These findings represent a critical mechanism in the health assessment of carbon-based pollutants, providing valuable insights into the atomic-level processes underlying airway epithelial injury, a primary cause of respiratory diseases associated with NPs exposure. Furthermore, the AKT/TMEM175 could serve as a promising tool for assessing airway epithelial damage induced by other carbon-contained pollutants.