ADAM17 deficiency by mature neutrophils has differential effects on L-selectin shedding (97.14)

Abstract

Abstract L-selectin directs neutrophils to sites of inflammation, and upon their activation, surface expression of the receptor is rapidly downregulated by ectodomain shedding. ADAM17 (also known as Tumor necrosis factor-alpha-converting enzyme or TACE) is a sheddase of L-selectin; however, Adam17 gene-targeting (ADAM17−/−) in mice is perinatal lethal and its role in L-selectin shedding by mature leukocytes has not been determined. This issue was addressed here by generating radiation-chimeric mice reconstituted with ADAM17−/−fetal liver progenitor cells. ADAM17-deficient neutrophils, monocytes and lymphocytes failed to shed L-selectin in response to PMA, as did neutrophils infiltrating the inflamed peritoneum. In addition, the lack of functional ADAM17 resulted in significantly increased levels of L-selectin surface expression by leukocytes in peripheral blood, suggesting the sheddase is also involved in the constitutive cleavage of L-selectin. Interestingly, it seems that ADAM17 is not required in all manners of L-selectin turnover. Plasma levels of soluble L-selectin were similar between ADAM17−/−chimeric and control mice, as was the shedding of L-selectin by neutrophils undergoing apoptosis. The latter process, however, was diminished by a metalloprotease inhibitor (TAPI-0), indicating the involvement of a metalloprotease sheddase other than ADAM17. Our data is the first to demonstrate that L-selectin’s surface density on neutrophils is regulated by ADAM17, but homeostatic cleavage of L-selectin is not. This work is supported by grant HL61613 (B.W.) from the National Institutes of Health.