{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T08:03:38Z","timestamp":1793261018406,"version":"4.5.0"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T00:00:00Z","timestamp":1745798400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Hypoxia plays a pivotal role in modulating immune responses, especially in neutrophils, which are essential components of the innate immune system. Hypoxia-inducible factor (HIF)-1\u03b1, a key transcription factor in hypoxic adaptation, regulates cellular metabolism and inflammatory responses. However, the impact of HIF-1\u03b1-dependent glycolysis on the formation of neutrophil extracellular traps (known as NETosis) under hypoxic conditions remains unclear.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We employed two established neutrophil models, neutrophils isolated from human whole blood and DMSO-induced dHL-60 cells, to explore the role of HIF-1\u03b1 in regulating glycolysis and its influence on NETosis under hypoxic conditions. We utilized western blotting, immunofluorescence staining, ELISA, and flow cytometry to evaluate the expression of key glycolytic enzymes and NETosis markers under hypoxia. Additionally, the effects of inhibiting HIF-1\u03b1 with LW6 and blocking the glycolytic pathway with Bay-876 were investigated.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>HIF-1\u03b1-dependent glycolysis, through the upregulation of key glycolytic enzymes, significantly enhances NETosis under hypoxic conditions. Pharmacological inhibition of HIF-1\u03b1 with LW6 and glycolytic blockade with Bay-876 markedly reduced NETosis, underscoring the crucial role of metabolic reprogramming in neutrophil function during hypoxia.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>This study provides novel insights into the interplay between metabolic reprogramming and NETosis in response to hypoxic stress. We identify HIF-1\u03b1-dependent glycolysis as a key driver of NETs formation, advancing our understanding of the mechanisms underlying hypoxia-related inflammatory diseases. These findings also suggest that targeting metabolic pathways may offer potential therapeutic strategies for modulating immune responses in hypoxia-associated disorders.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1583587","type":"journal-article","created":{"date-parts":[[2025,4,28]],"date-time":"2025-04-28T01:32:55Z","timestamp":1745803975000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":35,"title":["In vitro study: HIF-1\u03b1-dependent glycolysis enhances NETosis in hypoxic conditions"],"prefix":"10.3389","volume":"16","author":[{"given":"Yi","family":"Ye","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanjun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiying","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juanli","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziqi","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tana","family":"Wuren","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ri-Li","family":"Ge","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,4,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra0910283","article-title":"Hypoxia and inflammation","volume":"364","author":"Eltzschig","year":"2011","journal-title":"N Engl J Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1089\/ham.2024.0107","article-title":"Medical problems of chronic hypoxia in highlanders living on the tibetan plateau","volume":"1","author":"Ge","year":"2025","journal-title":"High Alt Med Biol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines9030260","article-title":"Hypoxia\/HIF modulates immune responses","volume":"9","author":"Chen","year":"2021","journal-title":"Biomedicines"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14092291","article-title":"Hypoxia as a modulator of inflammation and immune response in cancer","volume":"14","author":"Castillo-Rodr\u00edguez","year":"2022","journal-title":"Cancers (Basel)"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.103","article-title":"Regulation of immunity and inflammation by hypoxia in immunological niches","volume":"17","author":"Taylor","year":"2017","journal-title":"Nat Rev Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fphys.2021.676782","article-title":"Hypoxia and inflammation: insights from high-altitude physiology","volume":"12","author":"Pham","year":"2021","journal-title":"Front Physiol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1113\/eph.v106.8","article-title":"The deleterious effects of acute hypoxia on microvascular and large vessel endothelial function","volume":"106","author":"Jones","year":"2021","journal-title":"Exp Physiol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00324","article-title":"Oxygen levels and immunological studies","volume":"8","author":"Zenewicz","year":"2017","journal-title":"Front Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1318345110","article-title":"Hypoxia and inflammation are two sides of the same coin","volume":"110","author":"Bartels","year":"2013","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2020.08.002","article-title":"The role of HIF in immunity and inflammation","volume":"32","author":"McGettrick","year":"2020","journal-title":"Cell Metab"},{"key":"B11","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1186\/ar2632","article-title":"Hypoxia. 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