Leukocytes require ADAM10 but not ADAM17 for their migration and inflammatory recruitment into the alveolar space

Inflammation is a key process in various diseases, characterized by leukocyte recruitment to the inflammatory site. This study investigates the role of a disintegrin and a metalloproteinase (ADAM) 10 and ADAM17 for leukocyte migration in vitro and in a murine model of acute pulmonary inflammation. I...

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Bibliographic Details
Published in:	Blood Vol. 123; no. 26; pp. 4077 - 4088
Main Authors:	Pruessmeyer, Jessica, Hess, Franz Martin, Alert, Henriette, Groth, Esther, Pasqualon, Tobias, Schwarz, Nicole, Nyamoya, Stella, Kollert, Jos, van der Vorst, Emiel, Donners, Marjo, Martin, Christian, Uhlig, Stefan, Saftig, Paul, Dreymueller, Daniela, Ludwig, Andreas
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 26-06-2014
Subjects:	Acute Disease ADAM Proteins - genetics ADAM Proteins - metabolism ADAM10 Protein ADAM17 Protein Amyloid Precursor Protein Secretases - genetics Amyloid Precursor Protein Secretases - metabolism Animals Cell Line, Tumor Cell Movement HEK293 Cells Humans Inflammation - chemically induced Inflammation - enzymology Inflammation - genetics Inflammation - pathology Lipopolysaccharides - toxicity Membrane Proteins - genetics Membrane Proteins - metabolism Mice Mice, Knockout Neutrophil Infiltration Neutrophils - enzymology Neutrophils - pathology Pneumonia - chemically induced Pneumonia - enzymology Pneumonia - genetics Pneumonia - pathology Pulmonary Alveoli - enzymology Pulmonary Alveoli - pathology Pulmonary Edema - chemically induced Pulmonary Edema - enzymology Pulmonary Edema - genetics Pulmonary Edema - pathology
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Summary:	Inflammation is a key process in various diseases, characterized by leukocyte recruitment to the inflammatory site. This study investigates the role of a disintegrin and a metalloproteinase (ADAM) 10 and ADAM17 for leukocyte migration in vitro and in a murine model of acute pulmonary inflammation. Inhibition experiments or RNA knockdown indicated that monocytic THP-1 cells and primary human neutrophils require ADAM10 but not ADAM17 for efficient chemokine-induced cell migration. Signaling and adhesion events that are linked to cell migration such as p38 and ρ GTPase-family activation, F-actin polymerization, adhesion to fibronectin, and up-regulation of α5 integrin were also dependent on ADAM10 but not ADAM17. This was confirmed with leukocytes isolated from mice lacking either ADAM10 or ADAM17 in all hematopoietic cells (vav 1 guanine nucleotide exchange factor [Vav]-Adam10−/− or Vav-Adam17−/− mice). In lipopolysaccharide-induced acute pulmonary inflammation, alveolar recruitment of neutrophils and monocytes was transiently increased in Vav-Adam17−/− but steadily reduced in Vav-Adam10−/− mice. This deficit in alveolar leukocyte recruitment was also observed in LysM-Adam10−/− mice lacking ADAM10 in myeloid cells and correlated with protection against edema formation. Thus, with regard to leukocyte migration, leukocyte-expressed ADAM10 but not ADAM17 displays proinflammatory activities and may therefore serve as a target to limit inflammatory cell recruitment. •ADAM10 but not ADAM17 on leukocytes is essential for chemokine-induced signaling, adhesion, cytoskeletal rearrangement, and migration.•Leukocyte-expressed ADAM10 promotes leukocyte recruitment and edema formation in a murine model of acute pulmonary inflammation.
ISSN:	0006-4971 1528-0020
DOI:	10.1182/blood-2013-09-511543