Abstract
ADAM17 is a transmembrane protease expressed by most cells in humans and mice that cleaves cell surface substrates primarily in a cis manner, a process referred to as ectodomain shedding. ADAM17 has numerous substrates and plays a broad role in various physiological processes, including as a key regulator of inflammation. At this time, little is known about ADAM17 expression and function in dogs. A well-established ADAM17 substrate is the leukocyte adhesion protein CD62L (L-selectin). We show that a selective inhibitor of ADAM17, but not an inhibitor of its most closely related family member ADAM10, blocks CD62L shedding upon canine neutrophil activation. We also tested several anti-human ADAM17 monoclonal antibodies (mAbs) for staining canine neutrophils. Although most did not recognize canine neutrophils, the mAbs MEDI3622 and D1(A12) did. They also blocked the downregulation of CD62L upon neutrophil activation. MEDI3622 is a human IgG antibody and we found that a canine chimeric version of this mAb also blocked CD62L shedding by canine leukocytes. Taken together, our findings provide the first direct evidence of ADAM17 expression and sheddase activity in dogs, establishing a potential therapeutic target for various inflammatory disorders.
Original language | English (US) |
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Article number | 110162 |
Journal | Veterinary immunology and immunopathology |
Volume | 231 |
DOIs | |
State | Published - Jan 2021 |
Bibliographical note
Funding Information:We would like to thank Kathy Stuebner and Amber Winter from the University of Minnesota, College of Veterinary Medicine, Clinical Investigation Center for assistance in acquiring canine peripheral blood samples, Taylor DePauw with flow cytometry assistance, Dr. Jianming Wu for his assistance with the figures and copy editing the manuscript. This work was supported by the National Institutes of Health [grant number HL128580 ]. KS was supported by a Howard Hughes Medical Institute and Burroughs Wellcome Fund Medical Research Fellowship . CAM and KS were supported by the Office of the Director of the NIH , award number T35OD011118.
Funding Information:
We would like to thank Kathy Stuebner and Amber Winter from the University of Minnesota, College of Veterinary Medicine, Clinical Investigation Center for assistance in acquiring canine peripheral blood samples, Taylor DePauw with flow cytometry assistance, Dr. Jianming Wu for his assistance with the figures and copy editing the manuscript. This work was supported by the National Institutes of Health [grant number HL128580]. KS was supported by a Howard Hughes Medical Institute and Burroughs Wellcome Fund Medical Research Fellowship. CAM and KS were supported by the Office of the Director of the NIH, award number T35OD011118.
Publisher Copyright:
© 2020 Elsevier B.V.
Keywords
- Canine
- Inflammation
- Metalloprotease
- Neutrophil