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

Haiyun Wei; Chao Chen; Fanglin Di; Changhua Sun; Xinzhi Wang; Meng Sun; Natong Liu; Min Zhang; Meng Li; Jie Zhang; Shuping Zhang; Xue Liang

doi:10.1016/j.envpol.2024.124130

PM_2.5-induced ferroptosis by Nrf2/Hmox1 signaling pathway led to inflammation in microglia

Environ Pollut. 2024 May 8:352:124130. doi: 10.1016/j.envpol.2024.124130. Online ahead of print.

Authors

Haiyun Wei¹, Chao Chen², Fanglin Di², Changhua Sun³, Xinzhi Wang⁴, Meng Sun⁵, Natong Liu⁴, Min Zhang², Meng Li⁵, Jie Zhang⁶, Shuping Zhang⁶, Xue Liang⁷

Affiliations

¹ School of Public Health, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China; Medical Science and Technology Innovation Center, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China.
² Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China.
³ Shandong Center for Disease Control and Prevention, Jinan, Shandong, 250014, China.
⁴ School of Public Health, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China.
⁵ Department of Neurosurgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, 250014, China.
⁶ Medical Science and Technology Innovation Center, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China; Biomedical Sciences College & Shandong Medicinal Biotechnology Centre, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China.
⁷ School of Public Health, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China; Medical Science and Technology Innovation Center, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China. Electronic address: liangxue@sdfmu.edu.cn.

PMID: 38729511
DOI: 10.1016/j.envpol.2024.124130

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 (PM_2.5), via oropharyngeal aspiration at two ambient equivalent concentrations. The Y-maze results showed that PM_2.5 exposure in mice would lead to the damage in hippocampal-dependent working memory. In addition, cell neuroinflammation, microglial activation were detected in hippocampus of PM_2.5-exposure mice. To confirm the underlying mechanism, the microarray assay was conducted to screen the differentially expressed genes (DEGs) in microglia after PM_2.5 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 PM_2.5 exposure for 24 h. And PM_2.5 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 PM_2.5 resulted in the ferroptosis by causing iron overload through Nrf2/Hmox1 signaling pathway, which could account for the inflammation in microglia.

Keywords: Ferroptosis; Fine particulate matter; Heme oxygenase-1; Inflammation; Microglia.