HIF-1α Pathway Orchestration by LCN2: A Key Player in Hypoxia-Mediated Colitis Exacerbation.
INFLAMMATION（2024）
National Institution of Drug Clinical Trial
Abstract
In this study, we investigated the role of hypoxia in the development of chronic inflammatory bowel disease (IBD), focusing on its impact on the HIF-1α signaling pathway through the upregulation of lipocalin 2 (LCN2). Using a murine model of colitis induced by sodium dextran sulfate (DSS) under hypoxic conditions, transcriptome sequencing revealed LCN2 as a key gene involved in hypoxia-mediated exacerbation of colitis. Bioinformatics analysis highlighted the involvement of crucial pathways, including HIF-1α and glycolysis, in the inflammatory process. Immune infiltration analysis demonstrated the polarization of M1 macrophages in response to hypoxic stimulation. In vitro studies using RAW264.7 cells further elucidated the exacerbation of inflammation and its impact on M1 macrophage polarization under hypoxic conditions. LCN2 knockout cells reversed hypoxia-induced inflammatory responses, and the HIF-1α pathway activator dimethyloxaloylglycine (DMOG) confirmed LCN2's role in mediating inflammation via the HIF-1α-induced glycolysis pathway. In a DSS-induced colitis mouse model, oral administration of LCN2-silencing lentivirus and DMOG under hypoxic conditions validated the exacerbation of colitis. Evaluation of colonic tissues revealed altered macrophage polarization, increased levels of inflammatory factors, and activation of the HIF-1α and glycolysis pathways. In conclusion, our findings suggest that hypoxia exacerbates colitis by modulating the HIF-1α pathway through LCN2, influencing M1 macrophage polarization in glycolysis. This study contributes to a better understanding of the mechanisms underlying IBD, providing potential therapeutic targets for intervention.
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Key words
chronic inflammatory bowel disease,hypoxia,HIF-1α signaling pathway,lipocalin 2,M1 macrophages,glycolysis
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