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During Acute Lung Injury Extracellular Matrix Protein Degradation Of ADAM9 Is a Novel Product of Polymorphonuclear Neutrophils: Regulation of Expression and Contributions to Extracellular Matrix Protein Degradation This information is current as during Acute Lung Injury of September 30, 2021. Robin Roychaudhuri, Anja H. Hergrueter, Francesca Polverino, Maria E. Laucho-Contreras, Kushagra Gupta, Niels Borregaard and Caroline A. Owen J Immunol 2014; 193:2469-2482; Prepublished online 25 Downloaded from July 2014; doi: 10.4049/jimmunol.1303370 http://www.jimmunol.org/content/193/5/2469 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2014/07/25/jimmunol.130337 Material 0.DCSupplemental References This article cites 66 articles, 27 of which you can access for free at: http://www.jimmunol.org/content/193/5/2469.full#ref-list-1 by guest on September 30, 2021 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology ADAM9 Is a Novel Product of Polymorphonuclear Neutrophils: Regulation of Expression and Contributions to Extracellular Matrix Protein Degradation during Acute Lung Injury Robin Roychaudhuri,*,1 Anja H. Hergrueter,*,1 Francesca Polverino,*,†,‡ Maria E. Laucho-Contreras,* Kushagra Gupta,* Niels Borregaard,x and Caroline A. Owen*,† A disintegrin and a metalloproteinase domain (ADAM) 9 is known to be expressed by monocytes and macrophages. In this study, we report that ADAM9 is also a product of human and murine polymorphonuclear neutrophils (PMNs). ADAM9 is not synthesized de novo by circulating PMNs. Rather, ADAM9 protein is stored in the gelatinase and specific granules and the secretory vesicles of human PMNs. Unstimulated PMNs express minimal quantities of surface ADAM9, but activation of PMNs with degranulating Downloaded from agonists rapidly (within 15 min) increases PMN surface ADAM9 levels. Human PMNs produce small quantities of soluble forms of ADAM9. Surprisingly, ADAM9 degrades several extracellular matrix (ECM) proteins, including fibronectin, entactin, laminin, and insoluble elastin, as potently as matrix metalloproteinase-9. However, ADAM9 does not degrade types I, III, or IV collagen or denatured collagens in vitro. To determine whether Adam9 regulates PMN recruitment or ECM protein turnover during inflam- matory responses, we compared wild-type and Adam92/2 mice in bacterial LPS- and bleomycin-mediated acute lung injury (ALI). Adam9 lung levels increase 10-fold during LPS-mediated ALI in wild-type mice (due to increases in leukocyte-derived Adam9), http://www.jimmunol.org/ but Adam9 does not regulate lung PMN (or macrophage) counts during ALI. Adam9 increases mortality, promotes lung injury, reduces lung compliance, and increases degradation of lung elastin during LPS- and/or bleomycin-mediated ALI. Adam9 does not regulate collagen accumulation in the bleomycin-treated lung. Thus, ADAM9 is expressed in an inducible fashion on PMN surfaces where it degrades some ECM proteins, and it promotes alveolar–capillary barrier injury during ALI in mice. The Journal of Immunology, 2014, 193: 2469–2482. disintegrin and metalloproteinase (MP) domain (ADAM) rich and an epidermal growth factor-like domain that may promote ∼ proteinases are a family of 30 type I transmembrane cell–cell fusion and/or regulate cell adhesion, 5) a transmembrane by guest on September 30, 2021 A proteins belonging to the zinc-dependent MP superfamily. domain that anchors ADAMs to cell surfaces, and 6) a cytoplasmic They are characterized by a multidomain structure that includes: 1) tail that can participate in intracellular signaling (1, 2). a pro-domain that maintains the MP domain in a latent form, 2) an ADAM9 (MDC-9/Meltrin-g) is expressed by monocytes (3), MP domain, 3) a disintegrin domain that binds integrins to regulate activated macrophages (4), fibroblasts (5), epithelial cells (6), acti- cell–cell or cell–matrix adhesion and/or migration, 4) a cysteine- vated vascular smooth muscle cells (7), and keratinocytes (8). It is also upregulated in these cells during pathologic processes and is *Division of Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital expressed by some tumor cells (9–12). ADAM9 is first synthesized † and Harvard Medical School, Boston, MA, 02115; Lovelace Respiratory Research as a precursor proenzyme (Mr of ∼110 kDa). It is then processed to Institute, Albuquerque, NM 87108; ‡Pulmonary Department, University of Parma, ∼ 43100 Parma, Italy; and xGranulocyte Research Laboratory, Department of Hema- an active form (Mr of 84 kDa) in the medial Golgi apparatus tology, University of Copenhagen, 2100 Copenhagen, Denmark by a furin-like pro-protein convertase that cleaves proADAM9 at 1R.R. and A.H.H. contributed equally to this paper. a consensus cleavage sequence between the pro and MP domains Received for publication December 17, 2013. Accepted for publication June 29, (13). Human and murine ADAM9 share 82% sequence homology at 2014. the amino acid level (14). This work was supported by National Institutes of Health Grants HL063137, Little is known about the activities of ADAM9 in regulating HL086814, HL111835, P01HL105339, P01HL114505, R0 HL055330, and physiologic or pathologic processes. Most is known about the R01AI111475, the Brigham and Women’s Hospital/Lovelace Respiratory Research Institute consortium, Flight Attendant Medical Research Institute Grant CIA 123046, function of ADAM9’s MP domain. ADAM9 is an active MP and and by the Danish Medical Research Council. has the characteristic consensus sequence (HEXXHXXGXXH) of Address correspondence and reprint requests to Dr. Caroline A. Owen, Division of MPs with three histidine residues binding the catalytically essen- Pulmonary and Critical Care Medicine, Brigham and Women’s Hospital and Harvard Medical School, 77 Avenue Louis Pasteur, 855B Harvard Institutes of Medicine tial zinc atom in the catalytic domain. ADAM9’s MP domain is Building, Boston, MA 02115. E-mail address: [email protected] not inhibited by tissue inhibitors of MPs (15), and its physio- The online version of this article contains supplemental material. logic inhibitors have not yet been identified. ADAM9’s MP domain Abbreviations used in this article: ADAM, a disintegrin and metalloproteinase do- cleaves a limited number of extracellular proteins, including 1) the main; ALI, acute lung injury; ARDS, acute respiratory distress syndrome; BAL, insulin B chain (13), 2) insulin-like growth factor binding proteins bronchoalveolar lavage; BALF, BAL fluid; ECM, extracellular matrix; i.t., intra- tracheal; KRPG buffer, Krebs–Ringer phosphate glucose buffer; MMP, matrix (16), 3) amyloid precursor protein at the a-secretase cleavage site in metalloproteinase; MP, metalloproteinase; MPO, myeloperoxidase; NE, neutrophil the non–amyloidogenic pathway (17), 4) ligands for the epidermal elastase; PAF, platelet-activating factor; PMN, polymorphonuclear neutrophil; growth factor receptor from cell surfaces (18), and 5) fibroblast proMMP, pro–matrix metalloproteinase; s, soluble; WT, wild-type. growth factor receptor 2iiib from tumor cell surfaces to contribute Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 to tumor cell growth and metastasis (11). ADAM9’s MP domain www.jimmunol.org/cgi/doi/10.4049/jimmunol.1303370 2470 ADAM9 IS A PMN PRODUCT THAT DEGRADES ECM PROTEINS also contributes to the formation of multinucleate giant cells from were isolated from the peripheral blood of healthy human volunteers using monocytes and macrophages by mechanisms that are not clear (3). the Ficoll-Hypaque method (24). Although there have been a small number of reports that a few Activation of PMNs ADAM proteinases cleave a limited number of extracellular matrix 7 (ECM) proteins (19, 20), it is not known whether ADAM9’s MP Human PMNs (10 /ml in PBS) were incubated for 30 min at 37˚C with or without PMA (0.3 mM), calcium ionophore (A23187; 1 mM), fMLP domain cleaves ECM proteins to promote tissue remodeling or injury. (1026–10211 M), IL-8 (1027–10210 M), or TNF-a (1027–10210 M). Other Less is known about the function of ADAM9’s other domains. aliquots of cells were incubated with or without fMLP (1027 M), TNF-a 2 2 The disintegrin domain of ADAM9 binds to various integrins, (10 7 M), or IL-8 (10 7 M) at 37˚C for up to 120 min. To test whether including: 1) a b integrin to promote adhesion of fibroblast cell agonists have synergistic or additive effects on regulating surface ADAM9 6 1 levels on PMNs, we incubated human PMNs at 37˚C for 15 min with or lines (21); 2) a1, a3, a6, av, and b1 integrins to regulate adhesion without optimal concentrations of bacterial LPS from Escherichia coli 27 27 of human embryonic kidney-293 cells (6); and 3) b1 integrins on 0111B4 (100 ng/ml), PAF (10 M), or TNF-a (10 M), followed
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