Li Ying, Brazzell Jennifer, Herrera Amy, Walcheck Bruce
Department of Veterinary and Biomedical Sciences, University of Minnesota, St Paul, MN 55108, USA.
Blood. 2006 Oct 1;108(7):2275-9. doi: 10.1182/blood-2006-02-005827. Epub 2006 May 30.
L-selectin directs neutrophils to sites of inflammation, and upon their activation, surface expression of the receptor is rapidly down-regulated by ectodomain shedding. Tumor necrosis factor-alpha-converting enzyme (TACE, or ADAM17) is a sheddase of L-selectin; however, Adam17 gene targeting (ADAM17(DeltaZn/DeltaZn)) in mice is perinatal lethal and its role in L-selectin shedding by mature neutrophils has not been determined. This was addressed here by using radiation-chimeric mice reconstituted with ADAM17(DeltaZn/DeltaZn) fetal liver 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 absence of functional ADAM17 resulted in significantly increased levels of L-selectin surface expression by peripheral-blood leukocytes, indicating the sheddase also plays a role in the constitutive cleavage of L-selectin. Interestingly, not all manners of L-selectin turnover required ADAM17. Plasma L-selectin levels were similar between ADAM17(DeltaZn/DeltaZn)-chimeric and control mice, as was the shedding of L-selectin by neutrophils undergoing spontaneous apoptosis. The latter process, however, was diminished by a metalloprotease inhibitor, indicating the role of a sheddase other than ADAM17. Together, our data reveal that L-selectin's surface density on neutrophils is regulated by ADAM17, but homeostatic L-selectin cleavage is not.
L-选择素将中性粒细胞导向炎症部位，在它们被激活后，受体的表面表达通过胞外域脱落而迅速下调。肿瘤坏死因子-α转化酶（TACE，或ADAM17）是L-选择素的一种脱落酶；然而，小鼠中的Adam17基因靶向（ADAM17(DeltaZn/DeltaZn)）在围产期是致死性的，其在成熟中性粒细胞介导的L-选择素脱落中的作用尚未确定。本文通过使用用ADAM17(DeltaZn/DeltaZn)胎肝细胞重建的辐射嵌合小鼠来解决这一问题。缺乏ADAM17的中性粒细胞、单核细胞和淋巴细胞在受到佛波酯刺激时无法脱落L-选择素，浸润发炎腹膜的中性粒细胞也是如此。此外，功能性ADAM17的缺失导致外周血白细胞表面L-选择素表达水平显著增加，这表明该脱落酶在L-选择素的组成性裂解中也起作用。有趣的是，并非L-选择素周转的所有方式都需要ADAM17。ADAM17(DeltaZn/DeltaZn)嵌合小鼠和对照小鼠之间的血浆L-选择素水平相似，经历自发凋亡的中性粒细胞的L-选择素脱落情况也是如此。然而，后一过程被一种金属蛋白酶抑制剂减弱，这表明存在一种不同于ADAM17的脱落酶。总之，我们的数据表明，中性粒细胞上L-选择素的表面密度受ADAM17调节，但稳态下L-选择素的裂解不受其调节。
