Untangling the role of ER stress and membrane lipid imbalance in fine particulate matter exposure

The progression of human activities produces huge quantities of pollutants that have adverse effects on the environment and human health. Air pollution is a complex mix of substances that comprises also particulate matter (PM), a mixture of solid and liquid particles. PM 2.5, composed by fine particles with diameter of 2.5 μm or smaller, is particularly harmful to human health as it can invade the deepest parts of the airways and deposit, causing damage to the respiratory system. In addition, inhaled PM2.5 can easily reach the bloodstream, thus contributing to the onset of severe life-threatening disorders. PM2.5 exposure affects fundamental cellular processes, but the precise mechanisms of its toxicity remain poorly understood. Moreover, many of the published studies evaluating PM2.5 effect on cell biology used exposure levels significantly higher than those that can be encountered in real world environments, even the most polluted. Studies have suggested that exposure to PM2.5 can disrupt endoplasmic reticulum (ER) homeostasis, inducing ER stress and Unfolded Protein Response (UPR) activation. Moreover, PM2.5 exposure has been linked to dyslipidemia in animal models and in human subjects. Interestingly, the ER is the main site for membrane biogenesis and lipid biosynthesis. Lipid composition, in turn, influences ER morphology, e.g., by regulating the balance between cisternae and tubules and influencing membrane fluidity. Despite these data, the potential link between ER dysfunction and altered lipid profiles upon PM2.5 exposure remains understudied. This study investigates the early effect of acute PM2.5 exposure on intracellular homeostasis, focusing in particular on ER alterations and lipid metabolism. Here we show that the insoluble portion of PM2.5, internalized by cells, is responsible for reducing cell viability. Acute exposure to PM2.5 sub-toxic concentrations alters lysosome homeostasis and ER morphology, as well as its ability to ensure proper calcium (Ca2+) handling. Lipidomic analysis revealed a profound alteration of membrane lipids. In particular, a relevant increase in the amount of long-chain ceramides was observed upon PM2.5 exposure. This is consistent with a change of membrane properties, including fluidity and membrane protein activity, potentially contributing to the observed alteration of ER morphology and functionality. Despite further investigation is required, these findings highlight the importance of ER dysfunction and lipid imbalance as early events triggered by PM2.5 exposure, providing insights into the mechanisms underlying PM2.5-induced diseases.