ADAM17 cleaves CD16b (FcγRIIIb) in human neutrophils

Yue Wang, Jianming Wu, Robert Newton, Nooshin S. Bahaie, Chunmei Long, Bruce Walcheck

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)680-685
Number of pages6
JournalBiochimica et Biophysica Acta - Molecular Cell Research
Volume1833
Issue number3
DOIs
StatePublished - Mar 2013

Bibliographical note

Funding Information:
This work was supported by funding from the American College of Rheumatology-Research and Education Foundation (JW) and from the National Institutes of Health ( AI082291 , BW). The authors wish to thank Dr. Daniel Bullard (University of Alabama at Birmingham) for his assistance with this study.

Keywords

  • ADAM17
  • Apoptosis
  • Fc receptor
  • Metalloprotease
  • Neutrophil

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