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Published on: March 9, 2010
Ectodomain shedding by ADAM17 (a disintegrin and metalloproteinase 17) in canine neutrophils
Kristin M Snyder1, Camille A McAloney2, Joshua S Montel2
1Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, Minnesota, USA; Animal Cancer Care and Research Program, University of Minnesota, St. Paul, MN, USA.
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.
Insights
Researchers found that ADAM17 (a disintegrin and metalloproteinase domain) is active in dogs and can be targeted to block CD62L shedding. This discovery offers a potential therapeutic strategy for canine inflammatory conditions.
Area of Science:
- Biochemistry
- Immunology
- Veterinary Medicine
Background:
- ADAM17 is a transmembrane protease involved in ectodomain shedding of cell surface proteins.
- ADAM17 regulates physiological processes, including inflammation, but its role in dogs is largely unknown.
- CD62L (L-selectin) is a leukocyte adhesion protein and a known substrate of ADAM17.
Purpose of the Study:
- To investigate the expression and function of ADAM17 in canine neutrophils.
- To determine if ADAM17 activity contributes to CD62L shedding in dogs.
- To identify potential therapeutic targets for canine inflammatory diseases.
Main Methods:
- Utilized a selective ADAM17 inhibitor to assess its effect on CD62L shedding in activated canine neutrophils.
- Tested anti-human ADAM17 monoclonal antibodies (mAbs) for their ability to stain and inhibit CD62L shedding in canine neutrophils.
- Developed and tested a canine chimeric version of a validated anti-ADAM17 mAb.
Main Results:
- A selective ADAM17 inhibitor blocked CD62L shedding in activated canine neutrophils, while an ADAM10 inhibitor did not.
- Two anti-human ADAM17 mAbs, MEDI3622 and D1(A12), recognized and stained canine neutrophils.
- These mAbs inhibited CD62L shedding and its downregulation upon neutrophil activation.
- A canine chimeric version of MEDI3622 also effectively blocked CD62L shedding by canine leukocytes.
Conclusions:
- This study provides the first direct evidence of ADAM17 expression and sheddase activity in dogs.
- ADAM17 plays a role in CD62L shedding in canine leukocytes.
- Targeting ADAM17 presents a potential therapeutic strategy for inflammatory disorders in dogs.
