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  3. H1N1 influenza virus infection through NRF2-KEAP1-GCLC pathway induces ferroptosis in nasal mucosal epithelial cells

H1N1 influenza virus infection through NRF2-KEAP1-GCLC pathway induces ferroptosis in nasal mucosal epithelial cells

  • Free Radic Biol Med. 2023 Aug 1:204:226-242. doi: 10.1016/j.freeradbiomed.2023.05.004.
Chengcheng Liu 1,  Xinhao Wu 2,  Xin Bing 2,  Wenwen Qi 2,  Fangyuan Zhu 3,  Na Guo 3,  Chengzhilin Li 3,  Xiaochen Gao 3,  Xue Cao 4,  Miaoqing Zhao 5,  Ming Xia 6
Affiliations

Affiliations

  • 1 Department of Central Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, China; Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China.
  • 2 Department of Otolaryngology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, China; Department of Otolaryngology, Shandong Provincial Hospital, Shandong University, China.
  • 3 Department of Otolaryngology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, China; Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China.
  • 4 Department of Otolaryngology, Shandong Provincial Hospital, Shandong University, China; Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China.
  • 5 Department of Pathology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China. Electronic address: [email protected].
  • 6 Department of Otolaryngology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, China; Department of Otolaryngology, Shandong Provincial Hospital, Shandong University, China; NHC Key Laboratory of Otorhinolaryngology, China; Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, 250117, China. Electronic address: [email protected].
PMID: 37146698 DOI: 10.1016/j.freeradbiomed.2023.05.004
Abstract

Influenza A virus can induce nasal inflammation by stimulating the death of nasal mucosa epithelium, however, the mechanism is not clear. In this study, to study the causes and mechanisms of nasal mucosa epithelial cell death caused by Influenza A virus H1N1, we isolated and cultured human nasal epithelial progenitor cells (hNEPCs) and exposed them to H1N1 virus after leading differentiation. Then we performed high-resolution untargeted metabolomics and RNAseq analysis of human nasal epithelial cells (hNECs) infected with H1N1 virus. Surprisingly, H1N1 virus Infection caused the differential expression of a large number of Ferroptosis related genes and metabolites in hNECs. Furthermore, we have observed a significant reduction in Nrf2/KEAP1 expression, GCLC expression, and abnormal glutaminolysis. By constructing overexpression vector of GCLC and the shRNAs of GCLC and Keap1, we determined the role of NRF2-KEAP1-GCLC signaling pathway in H1N1 virus-induced Ferroptosis. In addition, A Glutaminase antagonist, JHU-083, also demonstrated that glutaminolysis can regulate the NRF2-KEAP1-GCLC signal pathway and Ferroptosis. According to this study, H1N1 virus can induce the Ferroptosis of hNECs via the NRF2-KEAP1-GCLC signal pathway and glutaminolysis, leading to nasal mucosal epithelial inflammation. This discovery is expected to provide an attractive therapeutic target for viral-induced nasal inflammation.

Keywords

Ferroptosis; Glutaminolysis; Influenza A virus; Multiomics analysis; NRF2-KEAP1-GCLC; Nasal mucosal epithelial cells.

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