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. 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.
Institute of Pharmacology and Toxicology, Medical Faculty, and.
Jessica
J
Pruessmeyer
Institute of Pharmacology and Toxicology, Medical Faculty, and.
Franz Martin
FM
Hess
Institute of Pharmacology and Toxicology, Medical Faculty, and.
Henriette
H
Alert
Institute of Pharmacology and Toxicology, Medical Faculty, and.
Esther
E
Groth
Institute of Pharmacology and Toxicology, Medical Faculty, and.
Tobias
T
Pasqualon
Institute of Molecular and Cellular Anatomy, Medical Faculty, RWTH Aachen University, Aachen, Germany;
Nicole
N
Schwarz
Institute of Pharmacology and Toxicology, Medical Faculty, and.
Stella
S
Nyamoya
Institute of Pharmacology and Toxicology, Medical Faculty, and.
Jos
J
Kollert
Department of Pathology, Maastricht University, Maastricht, The Netherlands; and.
Emiel
E
van der Vorst
Department of Pathology, Maastricht University, Maastricht, The Netherlands; and.
Marjo
M
Donners
Institute of Pharmacology and Toxicology, Medical Faculty, and.
Christian
C
Martin
Institute of Pharmacology and Toxicology, Medical Faculty, and.
Stefan
S
Uhlig
Institute for Biochemistry, Christian-Albrechts-University Kiel, Kiel, Germany.
Paul
P
Saftig
Institute of Pharmacology and Toxicology, Medical Faculty, and.
Daniela
D
Dreymueller
Institute of Pharmacology and Toxicology, Medical Faculty, and.
Andreas
A
Ludwig
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D000208:Acute Disease; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D057809:HEK293 Cells; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008070:Lipopolysaccharides / Q000633:toxicity; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000201:enzymology* / Q000473:pathology; D011014:Pneumonia / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D011650:Pulmonary Alveoli / Q000201:enzymology* / Q000473:pathology; D011654:Pulmonary Edema / Q000139:chemically induced / Q000201:enzymology* / Q000235:genetics / Q000473:pathology
D008070:Lipopolysaccharides; D008565:Membrane Proteins; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; C491234:Adam10 protein, mouse; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse