title: ADAM17 cleaves CD16b (FcγRIIIb) in human neutrophils.
abstract: CD16b (FcγRIIIb) is exclusively expressed by human neutrophils and binds IgG in immune complexes. Cell surface CD16b undergoes efficient ectodomain shedding upon neutrophil activation and apoptosis. Indeed, soluble CD16b is present at high levels in the plasma of healthy individuals, which appears to be maintained by the daily turnover of apoptotic neutrophils. At this time, the principal protease responsible for CD16b shedding is not known. We show that CD16b plasma levels were significantly decreased in patients administered a selective inhibitor targeting the metalloproteases ADAM10 and ADAM17. Additional analysis with inhibitors selective for ADAM10 or ADAM17 revealed that only inhibition of ADAM17 significantly blocked the cleavage of CD16b following neutrophil activation and apoptosis. CD16b shedding by ADAM17 was further demonstrated using a unique ADAM17 function-blocking mAb and a cell-based ADAM17 reconstitution assay. Unlike human CD16, however, mouse CD16 did not undergo efficient ectodomain shedding upon neutrophil stimulation or apoptosis, indicating that this mechanism cannot be modeled in normal mice. Taken together, our findings are the first to directly demonstrate that ADAM17 cleaves CD16 in human leukocytes.
authors.affiliation: Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, MN 55108, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Wang
authors.forename: Jianming
authors.initials: J
authors.lastname: Wu
authors.forename: Robert
authors.initials: R
authors.lastname: Newton
authors.forename: Nooshin S
authors.initials: NS
authors.lastname: Bahaie
authors.forename: Chunmei
authors.initials: C
authors.lastname: Long
authors.forename: Bruce
authors.initials: B
authors.lastname: Walcheck
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D000072198:ADAM17 Protein; D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005434:Flow Cytometry; D058851:GPI-Linked Proteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D018375:Neutrophil Activation / Q000187:drug effects; D009504:Neutrophils / Q000378:metabolism* / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology*; D017452:Receptors, IgG / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid
chemical_list: C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D011480:Protease Inhibitors; D017452:Receptors, IgG; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C000606463:Adam17 protein, mouse