ADAM17 deficiency by mature neutrophils has differential effects on L-selectin shedding.
L-selectin directs neutrophils to sites of inflammation, and upon their activation, surface expression of the receptor is rapidly down-regulated by ectodomain shedding. Tumor necrosis factor-alpha-converting enzyme (TACE, or ADAM17) is a sheddase of L-selectin; however, Adam17 gene targeting (ADAM17(DeltaZn/DeltaZn)) in mice is perinatal lethal and its role in L-selectin shedding by mature neutrophils has not been determined. This was addressed here by using radiation-chimeric mice reconstituted with ADAM17(DeltaZn/DeltaZn) fetal liver cells. ADAM17-deficient neutrophils, monocytes, and lymphocytes failed to shed L-selectin in response to PMA, as did neutrophils infiltrating the inflamed peritoneum. In addition, the absence of functional ADAM17 resulted in significantly increased levels of L-selectin surface expression by peripheral-blood leukocytes, indicating the sheddase also plays a role in the constitutive cleavage of L-selectin. Interestingly, not all manners of L-selectin turnover required ADAM17. Plasma L-selectin levels were similar between ADAM17(DeltaZn/DeltaZn)-chimeric and control mice, as was the shedding of L-selectin by neutrophils undergoing spontaneous apoptosis. The latter process, however, was diminished by a metalloprotease inhibitor, indicating the role of a sheddase other than ADAM17. Together, our data reveal that L-selectin's surface density on neutrophils is regulated by ADAM17, but homeostatic L-selectin cleavage is not.
Li
Ying
Y
Department of Veterinary and Biomedical Sciences, University of Minnesota, St Paul, MN 55108, USA.
Brazzell
Jennifer
J
Herrera
Amy
A
Walcheck
Bruce
B
D051722:ADAM Proteins / Q000235:genetics* / Q000502:physiology*; D000072198:ADAM17 Protein; D000818:Animals; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D019041:L-Selectin / Q000378:metabolism*; D007962:Leukocytes / Q000378:metabolism; D008099:Liver / Q000196:embryology; D051379:Mice; D008810:Mice, Inbred C57BL; D018375:Neutrophil Activation; D009504:Neutrophils / Q000378:metabolism*; D017434:Protein Structure, Tertiary
D019041:L-Selectin; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse