{"id":69726,"date":"2026-07-11T01:42:01","date_gmt":"2026-07-10T23:42:01","guid":{"rendered":"https:\/\/inmuno.es\/index.php\/2026\/07\/11\/dll4-neutrophils-induce-alveolar-macrophages-to-cause-adam-17-mediated-endothelial-barrier-disruption-and-the-increase-of-icam1hicxcr1lo-neutrophils-in-sepsishui-jin-on-10-de-july-de-2026\/"},"modified":"2026-07-11T01:42:01","modified_gmt":"2026-07-10T23:42:01","slug":"dll4-neutrophils-induce-alveolar-macrophages-to-cause-adam-17-mediated-endothelial-barrier-disruption-and-the-increase-of-icam1hicxcr1lo-neutrophils-in-sepsishui-jin-on-10-de-july-de-2026","status":"publish","type":"post","link":"https:\/\/inmuno.es\/index.php\/2026\/07\/11\/dll4-neutrophils-induce-alveolar-macrophages-to-cause-adam-17-mediated-endothelial-barrier-disruption-and-the-increase-of-icam1hicxcr1lo-neutrophils-in-sepsishui-jin-on-10-de-july-de-2026\/","title":{"rendered":"DLL4+ Neutrophils Induce Alveolar Macrophages to Cause ADAM-17-mediated Endothelial Barrier Disruption and the Increase of ICAM1hiCXCR1lo Neutrophils in Sepsis\u200bHui Jin on 10 de July de 2026 at 10:00"},"content":{"rendered":"
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J Leukoc Biol<\/b>. 2026 Jul 10:qiag097. doi: 10.1093\/jleuko\/qiag097. Online ahead of print.<\/p>\n

ABSTRACT<\/b><\/p>\n

Sepsis remains a leading cause of death. Reverse migrated (RM) neutrophils, characterized as ICAM1hiCXCR1lo, have been recognized as a key driver of systemic inflammation and organ injury in sepsis. We have recently discovered a distinct 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, were shown to be 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 (rmDLL4), 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 neutrophils generation. Small-molecule inhibitor of ADAM17 effectively preserved pulmonary endothelial barrier integrity, and reduced ICAM1hiCXCR1lo neutrophils accumulation. Importantly, we have developed a novel DLL4-Notch1 inhibitory peptide (NDI) that effectively suppresses ADAM17 expression, restores JAM-C, and reduces ICAM1hiCXCR1lo neutrophils accumulation in sepsis. These findings identify DLL4+ neutrophils as a critical inflammatory mediator that exacerbate systemic inflammation and worsen sepsis, highlight the DLL4-Notch1-ADAM17 axis as a promising therapeutic target.<\/p>\n

PMID:42430668<\/a> | DOI:10.1093\/jleuko\/qiag097<\/a><\/p>\n<\/div>","protected":false},"excerpt":{"rendered":"

J Leukoc Biol. 2026 Jul 10:qiag097. doi: 10.1093\/jleuko\/qiag097. Online ahead of print. ABSTRACT Sepsis remains a leading cause of death. Reverse migrated (RM) neutrophils, characterized as ICAM1hiCXCR1lo, have been recognized as a key driver of systemic inflammation and organ injury in sepsis. We have recently discovered a distinct DLL4+ subset of neutrophils that accumulate in … Read more<\/a><\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[86,42],"tags":[],"class_list":["post-69726","post","type-post","status-publish","format-standard","hentry","category-journal-of-leukocyte-biology","category-publicaciones"],"_links":{"self":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/69726","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/comments?post=69726"}],"version-history":[{"count":0,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/69726\/revisions"}],"wp:attachment":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/media?parent=69726"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/categories?post=69726"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/tags?post=69726"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}