{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,30]],"date-time":"2026-10-30T19:51:45Z","timestamp":1793389905492,"version":"4.5.0"},"reference-count":128,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T00:00:00Z","timestamp":1776384000000},"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:p>Sepsis has a high incidence and mortality rate, bringing about a high global burden. Recent research has demonstrated that the S100A8\/A9\u2013NETosis feedback loop is considered a central regulator of sepsis. However, few studies have integrated these elements into a unified \u2018S100A8\/A9\u2013NETosis feedback loop\u2019. Meanwhile, a systematic description of this loop in the interaction between myeloid cells and platelets, as well as organ damage, has not been established. This review systematically proposes the S100A8\/A9\u2013NETosis positive feedback loop as a core pathological mechanism and explores its potential pathways in sepsis. Specifically, we examine how this loop drives neutrophil-mediated hyperinflammation, monocyte\/macrophage polarization, immune paralysis (mediated by dendritic cells and myeloid-derived suppressor cells), and immune thrombosis (triggered by platelets). We also evaluate how this loop contributes to organ-specific injury and discuss potential therapeutic strategies, providing new perspectives for sepsis treatment.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1790788","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T04:15:07Z","timestamp":1776399307000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["The S100A8\/A9\u2013NETosis feedback loop in sepsis: potential mechanisms, immune crosstalk, and therapeutic targeting"],"prefix":"10.3389","volume":"17","author":[{"given":"Sini","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Critical Care Medicine, Affiliated Hospital of Guangdong Medical University","place":["Zhanjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingying","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Affiliated Hospital of Guangdong Medical University","place":["Zhanjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahao","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Affiliated Hospital of Guangdong Medical University","place":["Zhanjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liehua","family":"Deng","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Affiliated Hospital of Guangdong Medical University","place":["Zhanjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanli","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Critical Care Medicine, Affiliated Hospital of Guangdong Medical University","place":["Zhanjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,4,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra2403213","article-title":"Sepsis and septic shock","volume":"391","author":"Meyer","year":"2024","journal-title":"N Engl J Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1007\/s00134-024-07694-z","article-title":"Sepsis: key insights, future directions, and immediate goals. 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