title: Adam17-dependent shedding limits early neutrophil influx but does not alter early monocyte recruitment to inflammatory sites.
abstract: TNF-α-converting enzyme (TACE, herein denoted as Adam17) proteolytically sheds several cell-surface inflammatory proteins, but the physiologic importance of the cleavage of these substrates from leukocyte subsets during inflammation is incompletely understood. In this study, we show that Adam17-null neutrophils have a 2-fold advantage in their initial recruitment during thioglycollate-induced peritonitis, and they roll slower and adhere more readily in the cremaster model than wild-type neutrophils. Although CD44 and ICAM-1 are both in vitro substrates of Adam17, their surface levels are not altered on Adam17-null neutrophils. In contrast, L-selectin levels are elevated up to 10-fold in Adam17-null circulating neutrophils, and their accelerated peritoneal influx, slower rolling, and increased adhesion in the cremaster muscle are dependent on L-selectin. Analysis of mixed chimeras shows that enhanced L-selectin levels and accelerated influx were both cell-intrinsic properties of neutrophils lacking Adam17. In contrast, Adam17-null monocytes display no acceleration of infiltration into the peritoneum in spite of elevated L-selectin surface levels, and their peritoneal influx was independent of L-selectin. Therefore, our data demonstrate substrate and myeloid cell-type specificity of Adam17-mediated cleavage of its substrates, and show that neutrophils and monocytes use distinct mechanisms for infiltration of tissues.
authors.affiliation: Department of Pathology, University of Washington, Seattle, WA 98104, USA.
authors.forename: Jingjing
authors.initials: J
authors.lastname: Tang
authors.forename: Alexander
authors.initials: A
authors.lastname: Zarbock
authors.forename: Ivan
authors.initials: I
authors.lastname: Gomez
authors.forename: Carole L
authors.initials: CL
authors.lastname: Wilson
authors.forename: Craig T
authors.initials: CT
authors.lastname: Lefort
authors.forename: Anika
authors.initials: A
authors.lastname: Stadtmann
authors.forename: Bridgit
authors.initials: B
authors.lastname: Bell
authors.forename: Li-Chuan
authors.initials: LC
authors.lastname: Huang
authors.forename: Klaus
authors.initials: K
authors.lastname: Ley
authors.forename: Elaine W
authors.initials: EW
authors.lastname: Raines
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D000072198:ADAM17 Protein; D000818:Animals; D002448:Cell Adhesion / Q000276:immunology; D002465:Cell Movement / Q000276:immunology*; D002678:Chimera; D004195:Disease Models, Animal; D007140:Immunoglobulin Fab Fragments / Q000494:pharmacology; D007249:Inflammation / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D019041:L-Selectin / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009000:Monocytes / Q000166:cytology / Q000276:immunology*; D009504:Neutrophils / Q000166:cytology / Q000276:immunology*; D010538:Peritonitis / Q000139:chemically induced / Q000276:immunology / Q000378:metabolism; D013379:Substrate Specificity; D013864:Thioglycolates / Q000494:pharmacology
chemical_list: D007140:Immunoglobulin Fab Fragments; D013864:Thioglycolates; D019041:L-Selectin; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse