TY - JOUR
T1 - Leukocytes require ADAM10 but not ADAM17 for their migration and inflammatory recruitment into the alveolar space
AU - Pruessmeyer, Jessica
AU - Hess, Franz Martin
AU - Alert, Henriette
AU - Groth, Esther
AU - Pasqualon, Tobias
AU - Schwarz, Nicole
AU - Nyamoya, Stella
AU - Kollert, Jos
AU - van der Vorst, Emiel
AU - Donners, Marjo
AU - Martin, Christian
AU - Uhlig, Stefan
AU - Saftig, Paul
AU - Dreymueller, Daniela
AU - Ludwig, Andreas
PY - 2014/6/26
Y1 - 2014/6/26
N2 - 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 rho GTPase-family activation, F-actin polymerization, adhesion to fibronectin, and up-regulation of alpha(5) 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.
AB - 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 rho GTPase-family activation, F-actin polymerization, adhesion to fibronectin, and up-regulation of alpha(5) 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.
U2 - 10.1182/blood-2013-09-511543
DO - 10.1182/blood-2013-09-511543
M3 - Article
C2 - 24833351
SN - 0006-4971
VL - 123
SP - 4077
EP - 4088
JO - Blood
JF - Blood
IS - 26
ER -