ADAM17 cleaves CD16b (FcγRIIIb) in human neutrophils

• Published in: Biochimica et biophysica acta Vol. 1833; no. 3; pp. 680 - 685
• Main Authors: Wang, Yue, Wu, Jianming, Newton, Robert, Bahaie, Nooshin S., Long, Chunmei, Walcheck, Bruce
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.03.2013
• Subjects: ADAM Proteins - antagonists & inhibitors; ADAM Proteins - physiology; ADAM17; ADAM17 Protein; Amino Acid Sequence; Animals; Apoptosis; Blotting, Western; Fc receptor; Fibroblasts - cytology; Fibroblasts - drug effects; Fibroblasts - metabolism; Flow Cytometry; GPI-Linked Proteins - metabolism; Humans; Metalloprotease; Mice; Mice, Knockout; Molecular Sequence Data; Neutrophil; Neutrophil Activation - drug effects; Neutrophils - metabolism; Neutrophils - pathology; Protease Inhibitors - pharmacology; Receptors, IgG - metabolism; Sequence Homology, Amino Acid; Metalloprotease; ADAM; ADAM17; Fc receptor; Neutrophil; Apoptosis
• ISSN: 0167-4889; 0006-3002; 1879-2596; 1878-2434
• DOI: 10.1016/j.bbamcr.2012.11.027

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. [Display omitted] ► Plasma CD16 in humans is generated by ADAM protease activity. ► ADAM17 cleaves CD16a and CD16b in activated NK cells and neutrophils, respectively. ► CD16b undergoes ectodomain shedding in apoptotic neutrophils by ADAM17. ► Unlike human CD16, mouse CD16 is not efficiently regulated by ectodomain shedding.