Department 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.
Department of Veterinary and Biomedical Sciences, University of Minnesota, St. Paul, Minnesota, USA.
Vet Immunol Immunopathol. 2021 Jan;231:110162. doi: 10.1016/j.vetimm.2020.110162. Epub 2020 Nov 17.
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.
ADAM17 是一种跨膜蛋白酶，在人和小鼠的大多数细胞中表达，主要以顺式方式切割细胞表面底物，这一过程称为细胞外结构域脱落。ADAM17 有许多底物，在各种生理过程中发挥广泛作用，包括作为炎症的关键调节剂。目前，人们对 ADAM17 在犬中的表达和功能知之甚少。一个成熟的 ADAM17 底物是白细胞黏附蛋白 CD62L（L-选择素）。我们表明，一种选择性 ADAM17 抑制剂，但不是其最密切相关的家族成员 ADAM10 的抑制剂，可阻断犬中性粒细胞激活时 CD62L 的脱落。我们还测试了几种针对人 ADAM17 的单克隆抗体（mAb）来标记犬中性粒细胞。尽管大多数抗体不能识别犬中性粒细胞，但 mAb MEDI3622 和 D1(A12) 可以。它们还阻断了中性粒细胞激活时 CD62L 的下调。MEDI3622 是一种人 IgG 抗体，我们发现该 mAb 的犬嵌合版本也可阻断犬白细胞的 CD62L 脱落。总之，我们的研究结果提供了 ADAM17 在犬中表达和脱落酶活性的直接证据，为各种炎症性疾病建立了一个潜在的治疗靶点。
