{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T01:53:42Z","timestamp":1790646822327,"version":"4.1.0"},"reference-count":43,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,10,4]],"date-time":"2022-10-04T00:00:00Z","timestamp":1664841600000},"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":"\n Background and objective<\/jats:title>\n \n The correlation (Rs &gt; 0.7) of neutrophils expressing the dual endothelin1\/signal peptide receptor (DEspR+CD11b+\/CD66b+) with severity of hypoxemia (SF-ratio) and multi-organ failure (SOFA-score) in patients with acute respiratory distress syndrome (ARDS) suggest the hypothesis that the DEspR+ neutrophil-subset is an actionable therapeutic target in ARDS. To test this hypothesis, we conducted\n in vivo<\/jats:italic>\n studies to validate DEspR+ neutrophil-subset as therapeutic target and test efficacy of DEspR-inhibition in acute neutrophilic hyperinflammation models.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We performed tests in lipopolysaccharide (LPS)-induced acute neutrophilic inflammation in three species \u2013 human, rhesus macaque, rat \u2013 with increasing dose-dependent severity. We measured DEspR+CD66b+ neutrophils in bronchoalveolar lavage fluid (BALF) in healthy volunteers (HVs) 24-hours after segmental LPS-challenge by ChipCytometry, and DEspR+CD11b+ neutrophils in whole blood and BALF in an LPS-induced transient acute lung injury (ALI) model in macaques. We determined anti-DEspR antibody efficacy\n in vivo<\/jats:italic>\n in LPS-ALI macaque model and in high-mortality LPS-induced encephalopathy in hypertensive rats.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n ChipCytometry detected increased BALF total neutrophil and DEspR+CD66b+ neutrophil counts after segmental LPS-challenge compared to baseline (\n P<\/jats:italic>\n =0.034), as well as increased peripheral neutrophil counts and neutrophil-lymphocyte ratio (NLR) compared to pre-LPS level (\n P &lt;<\/jats:italic>\n 0.05). In the LPS-ALI macaque model, flow cytometry detected increased DEspR+ and DEspR[-] neutrophils in BALF, which was associated with moderate-severe hypoxemia. After determining pharmacokinetics of single-dose anti-DEspR[hu6g8] antibody, one-time pre-LPS anti-DEspR treatment reduced hypoxemia (\n P<\/jats:italic>\n =0.03) and neutrophil influx into BALF\n (P<\/jats:italic>\n =0.0001) in LPS-ALI\n vs<\/jats:italic>\n vehicle mock-treated LPS-ALI macaques.\n Ex vivo<\/jats:italic>\n live cell imaging of macaque neutrophils detected greater \u201cintrinsic adhesion to hard-surface\u201d in DEspR+\n vs<\/jats:italic>\n DEspR[-] neutrophils (\n P &lt;<\/jats:italic>\n 0.001). Anti-DEspR[hu6g8] antibody abrogated intrinsic high adhesion in DEspR+ neutrophils, but not in DEspR[-] neutrophils (\n P &lt;<\/jats:italic>\n 0.001). In the LPS-encephalopathy rat model, anti-DEspR[10a3] antibody treatment increased median survival (\n P<\/jats:italic>\n =0.0007) and exhibited brain target engagement and bioeffects.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n Detection of increased DEspR+ neutrophil-subset in human BALF after segmental LPS-challenge supports the correlation of circulating DEspR+ neutrophil counts with severity measure (SOFA-score) in ARDS. Efficacy and safety of targeted inhibition of DEspR+CD11b+ neutrophil-subset in LPS-induced transient-ALI and high-mortality encephalopathy models identify a potential therapeutic target for neutrophil-mediated secondary tissue injury.<\/jats:p>\n <\/jats:sec>","DOI":"10.3389\/fimmu.2022.1008390","type":"journal-article","created":{"date-parts":[[2022,10,5]],"date-time":"2022-10-05T04:57:39Z","timestamp":1664945859000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["\u201cRogue\u201d neutrophil-subset [DEspR+CD11b+\/CD66b+] immunotype is an actionable therapeutic target for neutrophilic inflammation-mediated tissue injury \u2013 studies in human, macaque and rat LPS-inflammation models"],"prefix":"10.3389","volume":"13","author":[{"given":"Saskia","family":"Carstensen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meike","family":"M\u00fcller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Glaiza L. 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