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The vitamin D\u2013binding protein (DBP) has been shown to significantly enhance chemotaxis to complement activation peptide C5a using purified proteins in vitro, and by ex vivo depletion of DBP in physiological fluids, but this function has not been determined in vivo. DBP null (\u2212\/\u2212) mice were used to investigate how a systemic absence of this plasma protein affects leukocyte recruitment in alveolitis models of lung inflammation. DBP\u2212\/\u2212 mice had significantly reduced (\u223c50%) neutrophil recruitment to the lungs compared with their wild-type DBP+\/+ counterparts in three different alveolitis models, two acute and one chronic. The histology of DBP\u2212\/\u2212 mouse lungs also showed significantly less injury than wild-type animals. The chemotactic cofactor function of DBP appears to be selective for neutrophil recruitment, but, in contrast to previous in vitro results, in vivo DBP can enhance the activity of other chemoattractants, including CXCL1. The reduced neutrophil response in DBP\u2212\/\u2212 mice could be rescued to wild-type levels by administering exogenous DBP. Finally, in inflammatory fluids, DBP binds to G-actin released from damaged cells, and this complex may be the active chemotactic cofactor. To our knowledge, results show for the first time that DBP is a significant chemotactic cofactor in vivo and not specific for C5a, suggesting that this ubiquitous plasma protein may have a more significant role in neutrophil recruitment than previously recognized.<\/jats:p>","DOI":"10.4049\/jimmunol.1202941","type":"journal-article","created":{"date-parts":[[2013,6,11]],"date-time":"2013-06-11T04:02:41Z","timestamp":1370923361000},"page":"848-856","source":"Crossref","is-referenced-by-count":42,"title":["Neutrophil Recruitment to the Lung in Both C5a- and CXCL1-Induced Alveolitis Is Impaired in Vitamin D\u2013Binding Protein\u2013Deficient Mice"],"prefix":"10.1093","volume":"191","author":[{"given":"Glenda","family":"Trujillo","sequence":"first","affiliation":[{"name":"Department of Pathology, Stony Brook University School of Medicine , Stony Brook, NY 11794"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David M","family":"Habiel","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stony Brook University School of Medicine , Stony Brook, NY 11794"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lingyin","family":"Ge","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stony Brook University School of Medicine , Stony Brook, NY 11794"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mahalakshmi","family":"Ramadass","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stony Brook University School of Medicine , Stony Brook, NY 11794"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nancy E","family":"Cooke","sequence":"additional","affiliation":[{"name":"Department of Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104"},{"name":"Department of Genetics, Perelman School of Medicine, University of Pennsylvania , Philadelphia, PA 19104"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard R","family":"Kew","sequence":"additional","affiliation":[{"name":"Department of Pathology, Stony Brook University School of Medicine , Stony Brook, NY 11794"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2013,7,15]]},"reference":[{"key":"2025032405074440700_r1","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1146\/annurev-immunol-020711-074942","article-title":"Neutrophil function: from mechanisms to disease","volume":"30","author":"Amulic","year":"2012","journal-title":"Annu. 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Physiol."},{"key":"2025032405074440700_r35","doi-asserted-by":"crossref","first-page":"682","DOI":"10.1038\/nm1419","article-title":"Generation of C5a in the absence of C3: a new complement activation pathway","volume":"12","author":"Huber-Lang","year":"2006","journal-title":"Nat. Med."},{"key":"2025032405074440700_r36","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1189\/jlb.0703340","article-title":"Mouse bone marrow contains large numbers of functionally competent neutrophils","volume":"75","author":"Boxio","year":"2004","journal-title":"J. Leukoc. Biol."},{"key":"2025032405074440700_r37","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1084\/jem.137.2.387","article-title":"Leukocyte locomotion and chemotaxis: new methods for evaluation, and demonstration of a cell-derived chemotactic factor","volume":"137","author":"Zigmond","year":"1973","journal-title":"J. Exp. Med."},{"key":"2025032405074440700_r38","doi-asserted-by":"crossref","first-page":"PL5","DOI":"10.1126\/stke.2003.170.pl5","article-title":"Measuring chemotaxis and chemokinesis: the under-agarose cell migration assay","volume":"2003","author":"Heit","year":"2003","journal-title":"Sci. STKE"},{"key":"2025032405074440700_r39","doi-asserted-by":"crossref","first-page":"L379","DOI":"10.1152\/ajplung.00010.2008","article-title":"Animal models of acute lung injury","volume":"295","author":"Matute-Bello","year":"2008","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"2025032405074440700_r40","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/S0003-9861(02)00033-4","article-title":"Biochemical and preliminary crystallographic characterization of the vitamin D sterol- and actin-binding by human vitamin D-binding protein","volume":"402","author":"Swamy","year":"2002","journal-title":"Arch. Biochem. 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Care Med."},{"key":"2025032405074440700_r44","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/S0020-1383(99)00080-7","article-title":"Admission level of Gc-globulin predicts outcome after multiple trauma","volume":"30","author":"Dahl","year":"1999","journal-title":"Injury"},{"key":"2025032405074440700_r45","doi-asserted-by":"crossref","first-page":"17949","DOI":"10.1073\/pnas.0802572105","article-title":"Tonic inhibition of chemotaxis in human plasma","volume":"105","author":"Malawista","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032405074440700_r46","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1016\/S0006-291X(88)81330-5","article-title":"Evidence of a novel association of unsaturated fatty acids with Gc (vitamin D-binding protein)","volume":"153","author":"Williams","year":"1988","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"2025032405074440700_r47","first-page":"1","article-title":"Fatty acids bound to vitamin D-binding protein (DBP) from human and bovine sera","volume":"19","author":"Ena","year":"1989","journal-title":"Biochem. Int."},{"key":"2025032405074440700_r48","doi-asserted-by":"crossref","first-page":"6555","DOI":"10.1073\/pnas.1015605108","article-title":"Repulsive guidance molecule-A (RGM-A) inhibits leukocyte migration and mitigates inflammation","volume":"108","author":"Mirakaj","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025032405074440700_r49","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1016\/j.molimm.2005.07.023","article-title":"Selective inhibition of the C5a chemotactic cofactor function of the vitamin D binding protein by 1,25(OH)2 vitamin D3","volume":"43","author":"Shah","year":"2006","journal-title":"Mol. 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