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

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.

Functional identification of long non-coding RNAs induced by PM2.5 in microglia through microarray analysis.

As a dominating air pollutant, atmospheric fine particulate matter within 2.5 µm in diameter (PM2.5) has attracted increasing attention from the researchers all over the world, which will lead to various adverse effects on the central nervous system (CNS), yet the potential mechanism is unclear. In this study, the microglia (BV2 cell line) were exposed to different concentrations of PM2.5 (5, 10 and 20 µg/cm2) for 24 h. It was found that PM2.5 could result in adverse effects on microglia such as decreased cell viability, structural damage and even cell death. And it was reported that long non-coding RNAs (lncRNAs) could participate in multitudinous neurological diseases. Therefore, the microarray analysis was conducted in order to disclose the underlying neurotoxicity mechanism of PM2.5 by ascertaining the differentially expressed lncRNAs (DElncRNAs). The consequences indicated that the DElncRNAs were enriched in various biological pathways, including ferroptosis, IL-17 signaling pathway and NOD-like receptor signaling pathway. Moreover, the cis- and trans-regulated mRNAs by DElncRNAs as well as the corresponding transcriptional factors (TFs) were observed, such as CEBPA, MYC, MEIS1 and KLF4. In summary, our study supplies some candidate libraries and potential preventive target against PM2.5-induced toxicity through targeting lncRNAs. Furthermore, the post-transcriptional regulation will contribute to the future research on PM2.5-induced neurotoxicity.

The induction of ferroptosis in posthemorrhagic hydrocephalus.

Posthemorrhagic hydrocephalus (PHH) is a common neurological disease characterized by the disordered secretion of cerebrospinal fluid from the choroid plexus, ventricular dilation, and increased intracranial pressure after hemorrhage. Although these pathological processes are well established, the effective biomarkers for the diagnosis of PHH are still limited, largely because the underlying mechanisms-including cell death in the choroid plexus-are not well defined. Ferroptosis, a newly recognized type of programmed cell death, has been found to play a key role in a variety of pathologic conditions and diseases, including Parkinson's and Alzheimer's diseases. However, whether ferroptosis is induced in PHH is still unknown. In the current study, a rat model of PHH was established to investigate the induction of ferroptosis in PHH. Along with defects in memory and cognition, we observed that rats with experimentally induced PHH also demonstrated lipid peroxidation (a key marker of ferroptosis), as well as a significant increase and a significant decrease in two ferroptosis-specific genes, ACSL4 and SLC7A11, respectively. Thus, ferroptosis may serve as an auxiliary indicator for the diagnosis of PHH.