Adam17-dependent shedding limits early neutrophil influx but does not alter early monocyte recruitment to inflammatory sites.

Tang J, Zarbock A, Gomez I, Wilson CL, Lefort CT, Stadtmann A, Bell B, Huang LC, Ley K, Raines EW

Abstract

TNF-?-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.