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

by Selleckchem | Sep 06 2023

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.

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In this study, the researchers aimed to investigate the causes and mechanisms of nasal mucosa epithelial cell death induced by the H1N1 strain of the Influenza A virus. They isolated and cultured human nasal epithelial progenitor cells (hNEPCs), which were then exposed to the H1N1 virus after differentiation. The researchers employed high-resolution untargeted metabolomics and RNAseq analysis to study the infected human nasal epithelial cells (hNECs).

The results of the study revealed a surprising finding: H1N1 virus infection caused differential expression of numerous genes and metabolites related to ferroptosis in hNECs. Ferroptosis is a form of regulated cell death that is characterized by the accumulation of reactive oxygen species and lipid peroxides. The researchers observed a significant reduction in the expression of Nrf2/KEAP1 (nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1), as well as GCLC (glutamate-cysteine ligase catalytic subunit), which is involved in glutathione synthesis.

The abnormal regulation of the NRF2-KEAP1-GCLC signaling pathway and glutaminolysis, a process involving the breakdown of glutamine, were found to play a role in H1N1 virus-induced ferroptosis. To confirm this, the researchers constructed overexpression vectors of GCLC and used shRNAs (short hairpin RNAs) to silence GCLC and Keap1 expression. These experiments helped establish the involvement of the NRF2-KEAP1-GCLC signaling pathway in H1N1 virus-induced ferroptosis.

Furthermore, the researchers used a glutaminase antagonist called JHU-083, which inhibits the activity of an enzyme involved in glutaminolysis. The antagonist demonstrated that targeting glutaminolysis can regulate the NRF2-KEAP1-GCLC signal pathway and ferroptosis.

Based on these findings, the study suggests that the H1N1 virus induces ferroptosis in hNECs through the NRF2-KEAP1-GCLC signaling pathway and glutaminolysis, ultimately leading to nasal mucosal epithelial inflammation. The identification of this mechanism provides a promising therapeutic target for treating viral-induced nasal inflammation.