DLL4+ Neutrophils Induce Alveolar Macrophages to Cause ADAM-17-mediated Endothelial Barrier Disruption and the Increase of ICAM1hiCXCR1lo Neutrophils in Sepsis

Clicks: 33
ID: 320568
2026
Free PDF
Article Quality & Performance Metrics
Overall Quality
Not rated
Combines reader engagement with the AI quality analysis. This article has not been analysed, so there is no overall score — reader engagement is measured and shown alongside.
AI Quality Assessment
Not analyzed
Readership in this journal
Steady

Ranked #23 of 104 articles by views in journal of leukocyte biology

Most read Least read

Bar heights use a square-root scale.

Mint this article as an NFT
Not yet minted

Create a permanent, verifiable on-chain record of this article on the Scimatic Network. The NFT is held in your Journament account, and you can withdraw it to your own wallet at any time.

5 SUSD one-off · no wallet required
Sign in to mint
Abstract
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 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.
Reference Key
openalex_W7167948771 Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors Hui Jin, Saoirse Holland, Alok Jha, Monowar Aziz, Ping Wang
Are you one of these authors? Claim your profile
Journal journal of leukocyte biology
Year 2026
DOI
10.1093/jleuko/qiag097
URL
https://doi.org/10.1093/jleuko/qiag097
Keywords Keywords not found

Citations

No citations found. To add a citation, contact the admin at info@scimatic.org

Comments

No comments yet. Be the first to comment on this article.