{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:41Z","timestamp":1787028581589,"version":"build-2736575974"},"reference-count":28,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,22]],"date-time":"2026-02-22T00:00:00Z","timestamp":1771718400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82572495"],"award-info":[{"award-number":["82572495"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Key Project of National Natural Science Foundation of China","award":["U21A20370"],"award-info":[{"award-number":["U21A20370"]}]},{"DOI":"10.13039\/501100004608","name":"Natural Science Foundation of Jiangsu Province","doi-asserted-by":"publisher","award":["BK20240382"],"award-info":[{"award-number":["BK20240382"]}],"id":[{"id":"10.13039\/501100004608","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Suzhou Youth Science and Technology Project","award":["QNXM2025039"],"award-info":[{"award-number":["QNXM2025039"]}]},{"name":"Suzhou Municipal Hospital Model Worker Innovation Studio Young Talent Program"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The mechanisms underlying the generation of low-density neutrophils (LDNs), along with their phenotypic characteristics and role in organ injury during sepsis, remain poorly understood. This study utilized lipopolysaccharide (LPS) stimulation to mimic the septic microenvironment. LDNs and high-density neutrophils (HDNs) were isolated via density gradient centrifugation. Single-cell RNA sequencing, in vitro functional assays, and a cecal ligation and puncture (CLP) murine sepsis model were employed, alongside techniques including immunohistochemistry and flow cytometry, to investigate LDN heterogeneity and their role in sepsis-associated acute lung injury (ALI). Results demonstrated that LPS stimulation significantly increased the LDN proportion. Single-cell transcriptomics revealed substantial heterogeneity within LDNs, which exhibited a hyperactivated yet immunodeficient phenotype characterized by delayed apoptosis, impaired migration and phagocytosis, and a heightened capacity to suppress T-cell proliferation. In vivo, the NETosis inhibitor GSK484 reduced LDN generation and alleviated sepsis-associated ALI. In conclusion, sepsis induces the generation of immunodeficient LDNs via a NETosis-dependent pathway, which exacerbates lung injury. Targeting this pathway may represent a novel therapeutic strategy for sepsis.<\/jats:p>","DOI":"10.3390\/ijms27042042","type":"journal-article","created":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T08:58:21Z","timestamp":1771837101000},"page":"2042","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["NETosis-Dependent Generation of Immunodeficient Low-Density Neutrophils Exacerbates Sepsis-Induced Acute Lung Injury"],"prefix":"10.3390","volume":"27","author":[{"given":"Ran","family":"Sun","sequence":"first","affiliation":[{"name":"Research Center for Neutrophil Engineering Technology, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiamin","family":"Huang","sequence":"additional","affiliation":[{"name":"Research Center for Neutrophil Engineering Technology, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hangfei","family":"Jin","sequence":"additional","affiliation":[{"name":"Research Center for Neutrophil Engineering Technology, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao","family":"Wen","sequence":"additional","affiliation":[{"name":"Research Center for Neutrophil Engineering Technology, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Gao","sequence":"additional","affiliation":[{"name":"Research Center for Neutrophil Engineering Technology, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bingwei","family":"Sun","sequence":"additional","affiliation":[{"name":"Research Center for Neutrophil Engineering Technology, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215002, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"456","DOI":"10.3390\/epidemiologia5030032","article-title":"The Global Burden of Sepsis and Septic Shock","volume":"5","author":"Sangiorgio","year":"2024","journal-title":"Epidemiologia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1146\/annurev-physiol-061121-040214","article-title":"Sepsis-Induced Immunosuppression","volume":"84","author":"Torres","year":"2022","journal-title":"Annu. 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