{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T23:22:55Z","timestamp":1786663375179,"version":"build-2736575974"},"reference-count":42,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T00:00:00Z","timestamp":1751328000000},"content-version":"vor","delay-in-days":30,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100001448","name":"Alpha-1 Foundation","doi-asserted-by":"publisher","award":["AGR00019116"],"award-info":[{"award-number":["AGR00019116"]}],"id":[{"id":"10.13039\/100001448","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["RO1DK136011"],"award-info":[{"award-number":["RO1DK136011"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,6,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Alpha-1 antitrypsin, the most abundant protease inhibitor within the plasma, plays a crucial role in regulating neutrophils\u2019 function during inflammation. Alpha-1 antitrypsin deficiency is associated with excessive neutrophilic inflammation, yet the mechanisms underlying alpha-1 antitrypsin's role in neutrophil trafficking remain poorly understood. Here, we demonstrate alpha-1 antitrypsin is essential for maintaining neutrophil polarity, directional migration, and tissue infiltration during inflammation. Using alpha-1 antitrypsin-knockout mice, we found these mice present increased numbers of neutrophils in the bone marrow, impaired mobilization, and reduced liver neutrophil infiltration following lipopolysaccharide-induced systemic inflammation. Flow cytometry and immunohistochemistry revealed alpha-1 antitrypsin-knockout neutrophils had lower CD44 expression and defective F-actin polarization leading to impaired chemotaxis. Importantly, low expression of CD44 prevented efficient adhesion and transmigration of alpha-1 antitrypsin-knockout neutrophils across liver sinusoidal endothelial cells. Furthermore, chemotaxis assays showed alpha-1 antitrypsin-knockout neutrophils in alpha-1 antitrypsin\u2013deficient media displayed random motility and loss of directional migration toward fMLP (N-Formyl-Met-Leu-Phe), suggesting a critical role for alpha-1 antitrypsin in neutrophil trafficking. Additionally, plasma alpha-1 antitrypsin deficiency delayed neutrophils\u2019 rate of phagocytosis. Mechanistically, alpha-1 antitrypsin deficiency resulted in excessive ERK1\/2 (Extracellular Signal-Regulated Kinase 1\/2) activation in alpha-1 antitrypsin-knockout neutrophils, driving an interleukin-10-enriched environment while suppressing expression of CXCL1 (C-X-C Motif Chemokine Ligand 1) and CXCL10 (C-X-C Motif Chemokine Ligand 10), chemokines essential for neutrophil recruitment. Notably, exposure to wild-type plasma with sufficient alpha-1 antitrypsin restored ERK1\/2 activation, CD44 expression, and chemokine levels in alpha-1 antitrypsin-knockout neutrophils, confirming the role of circulating alpha-1 antitrypsin in maintaining neutrophil function. These findings highlight alpha-1 antitrypsin as a key regulator of neutrophil trafficking, adhesion, and immune signaling, with implications for alpha-1 antitrypsin deficiency-related inflammatory disorders.<\/jats:p>","DOI":"10.1093\/jleuko\/qiaf091","type":"journal-article","created":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T12:14:32Z","timestamp":1751372072000},"source":"Crossref","is-referenced-by-count":6,"title":["Alpha-1 antitrypsin modulates neutrophil phenotype and function: implications for inflammatory regulation"],"prefix":"10.1093","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-4920-8935","authenticated-orcid":false,"given":"Regina","family":"Oshins","sequence":"first","affiliation":[{"name":"Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida , College of Medicine, J. Hillis Miller Health Science Center, PO Box 100225, Gainesville, FL 32610-0225 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ishan","family":"Patel","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida , College of Medicine, J. Hillis Miller Health Science Center, PO Box 100225, Gainesville, FL 32610-0225 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laith","family":"Khartabil","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida , College of Medicine, J. Hillis Miller Health Science Center, PO Box 100225, Gainesville, FL 32610-0225 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Divya Sai","family":"Katikaneni","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida , College of Medicine, J. Hillis Miller Health Science Center, PO Box 100225, Gainesville, FL 32610-0225 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yogesh","family":"Scindia","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida , College of Medicine, J. Hillis Miller Health Science Center, PO Box 100225, Gainesville, FL 32610-0225 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4659-1622","authenticated-orcid":false,"given":"Nazli","family":"Khodayari","sequence":"additional","affiliation":[{"name":"Department of Medicine, Division of Pulmonary, Critical Care and Sleep Medicine, University of Florida , College of Medicine, J. Hillis Miller Health Science Center, PO Box 100225, Gainesville, FL 32610-0225 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,7,1]]},"reference":[{"key":"2025070409260724800_qiaf091-B1","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1186\/s12964-020-00648-0","article-title":"Alpha-1 antitrypsin deficient individuals have circulating extracellular vesicles with profibrogenic cargo","volume":"18","author":"Khodayari","year":"2020","journal-title":"Cell Commun Signal"},{"key":"2025070409260724800_qiaf091-B2","doi-asserted-by":"publisher","first-page":"379","DOI":"10.1046\/j.1365-2222.2001.01017.x","article-title":"Alpha-1-antitrypsin is present in the specific granules of human eosinophilic granulocytes","volume":"31","author":"Johansson","year":"2001","journal-title":"Clin Exp 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