{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T01:15:22Z","timestamp":1790126122691,"version":"4.0.1"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2026,7,1]],"date-time":"2026-07-01T00:00:00Z","timestamp":1782864000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R35GM118337"],"award-info":[{"award-number":["R35GM118337"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01HL076179"],"award-info":[{"award-number":["R01HL076179"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Sepsis remains a leading cause of death. Reverse migrated neutrophils, characterized as ICAM1hiCXCR1lo, have been recognized as a key driver of systemic inflammation and organ injury in sepsis. We discovered a distinct delta-like ligand 4\u2013positive (DLL4+) subset of neutrophils that accumulate in the lungs, contributing to lung injury; however, the underlying mechanism is less understood. In sepsis, ICAM1hiCXCR1lo neutrophils, being hyperactive, are detrimental. Here, we investigated how DLL4+ neutrophils activate alveolar macrophages (AMs) to cause endothelial cell barrier disruption and promote neutrophil reverse migration. AMs were treated with DLL4+ neutrophils or recombinant mouse DLL4, and a disintegrin and metalloprotease (ADAM17) generated by AMs was assessed at both mRNA and protein levels. Conditioned medium was subsequently applied to pulmonary vascular endothelial cells (pVECs); junctional adhesion molecule-C (JAM-C) protein was detected by Western blot assays; and ICAM1hiCXCR1lo neutrophils were detected by flow cytometry. We demonstrate that during sepsis induced by cecal ligation and puncture (CLP), DLL4+ neutrophils interact with AMs via the Notch1 pathway, leading to increase of ADAM17 expression. ADAM17 decreased JAM-C on pVECs, causing endothelial barrier disruption and ICAM1hiCXCR1lo neutrophil generation. A small-molecule inhibitor of ADAM17 effectively preserved pulmonary endothelial barrier integrity and reduced ICAM1hiCXCR1lo neutrophil accumulation. Importantly, we have developed a novel DLL4-Notch1 inhibitory peptide (NDI) that effectively suppresses ADAM17 expression, restores JAM-C, and reduces ICAM1hiCXCR1lo neutrophil accumulation in sepsis. These findings identify DLL4+ neutrophils as critical inflammatory mediators that exacerbate systemic inflammation and worsen sepsis, and highlight the DLL4-Notch1-ADAM17 axis as a promising therapeutic target.<\/jats:p>","DOI":"10.1093\/jleuko\/qiag097","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T11:47:34Z","timestamp":1783424854000},"source":"Crossref","is-referenced-by-count":1,"title":["DLL4+ neutrophils induce alveolar macrophages to cause ADAM-17\u2013mediated endothelial barrier disruption and the increase of ICAM1hiCXCR1lo neutrophils in sepsis"],"prefix":"10.1093","volume":"118","author":[{"given":"Hui","family":"Jin","sequence":"first","affiliation":[{"name":"Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research , 350 Community Dr., Manhasset, NY 11030 ,","place":["United 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and Molecular Medicine, Zucker School of Medicine , 350 Community Dr., Manhasset, NY 11030 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1557-0394","authenticated-orcid":false,"given":"Ping","family":"Wang","sequence":"additional","affiliation":[{"name":"Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research , 350 Community Dr., Manhasset, NY 11030 ,","place":["United States"]},{"name":"Departments of Surgery and Molecular Medicine, Zucker School of Medicine , 350 Community Dr., Manhasset, NY 11030 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,7,10]]},"reference":[{"key":"2026092207071088000_qiag097-B1","doi-asserted-by":"publisher","first-page":"801","DOI":"10.1001\/jama.2016.0287","article-title":"The Third International Consensus definitions for sepsis and septic shock 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