Particulate matter 2.5 stimulates pyroptosis and necroptosis via the p38 MAPK/Akt/NF-κB signaling pathway in human corneal epithelial cells

Abstract

Particulate matter 2.5 (PM_2.5) exposure poses significant health risks, particularly to the eyes. This study aimed to investigate the cytotoxic effects of PM_2.5 on human corneal epithelial cells (HCECs) and to elucidate the mechanisms involved in pyroptosis and necroptosis. HCECs were exposed to PM_2.5, and cytotoxicity, reactive oxygen species (ROS) levels, and the expression of pyroptosis- and necroptosis-related proteins were assessed. The roles of nuclear factor-kappa B (NF-κB) and nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome signaling pathways were also investigated. Exposure to PM_2.5 caused a dose-dependent decrease in cell viability, accompanied by significant NLRP3 inflammasome activation, leading to pyroptosis and the release of pro-inflammatory cytokines. Enhanced ROS generation and mitochondrial dysfunction have also been observed, along with indicators of necroptosis, such as increased levels of mixed-lineage kinase domain-like proteins. Importantly, activation of the NF-κB signaling pathway was crucial for these responses. The suppression of p38 mitogen-activated protein kinase (MAPK) and activation of protein kinase B (Akt) using pharmacological modulators SB203580 and SC79, respectively, significantly reduced PM_2.5-mediated cellular damage. These findings indicate that p38 MAPK inhibition and Akt activation are key regulatory mechanisms that help attenuate the deleterious effects of PM_2.5 on HCECs. In conclusion, our findings offer new insights into the mechanisms by which PM_2.5 induces pyroptosis and necroptosis in HCECs, especially by activating the NLRP3 inflammasome and NF-κB signaling pathways. The critical regulatory roles of p38 MAPK and Akt underscore their potential as therapeutic targets to alleviate PM-induced ocular damage.