PM2.5-induced ferroptosis by Nrf2/Hmox1 signaling pathway led to inflammation in microglia.

ABSTRACT

Particulate matter (PM) has been a dominant contributor to air contamination, which will enter the central nervous system (CNS), causing neurotoxicity. However, the biological mechanism is poorly identified. In this study, C57BL/6J mice were applied to evaluate the neurotoxicity of collected fine particulate matter (PM2.5), via oropharyngeal aspiration at two ambient equivalent concentrations. The Y-maze results showed that PM2.5 exposure in mice would lead to the damage in hippocampal-dependent working memory. In addition, cell neuroinflammation, microglial activation were detected in hippocampus of PM2.5-exposure mice. To confirm the underlying mechanism, the microarray assay was conducted to screen the differentially expressed genes (DEGs) in microglia after PM2.5 exposure, and the results indicated the enrichment of DEGs in ferroptosis pathways. Furthermore, Heme oxygenase-1 (Hmox1) was found to be one of the most remarkably upregulated genes after PM2.5 exposure for 24 h. And PM2.5 exposure induced ferroptosis with iron accumulation through heme degradation by Nrf2-mediated Hmox1 upregulation, which could be eliminated by Nrf2-inhibition. Meanwhile, Hmox1 antagonist zinc protoporphyrin IX (ZnPP) could protect BV2 cells from ferroptosis. The results taken together indicated that PM2.5 resulted in the ferroptosis by causing iron overload through Nrf2/Hmox1 signaling pathway, which could account for the inflammation in microglia.