ADAM17 cleaves CD16b (FcγRIIIb) in human neutrophils.
ADAM17 cleaves CD16b (FcγRIIIb) in human neutrophils.
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DOI：
10.1016/j.bbamcr.2012.11.027
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发表时间：
2013-03
影响因子：
5.1
通讯作者：
Walcheck, Bruce
中科院分区：
文献类型：
--
作者：
Wang, Yue;Wu, Jianming;Newton, Robert;Bahaie, Nooshin S.;Long, Chunmei;Walcheck, Bruce
CD16 b（FcγRIIIb）仅由人中性粒细胞表达，并结合免疫复合物中的IgG。细胞表面CD16 b在中性粒细胞活化和凋亡后经历有效的胞外域脱落。事实上，可溶性CD 16 b在健康个体的血浆中以高水平存在，这似乎是通过凋亡中性粒细胞的每日更新来维持的。此时，负责CD16b脱落的主要蛋白酶尚不清楚。我们发现，CD16b血浆水平显着降低患者给予靶向金属蛋白酶ADAM 10和ADAM 17的选择性抑制剂。对ADAM10或ADAM17选择性抑制剂的进一步分析显示，只有抑制ADAM17才能显著阻断中性粒细胞活化和凋亡后CD16 b的裂解。使用独特的ADAM 17功能阻断mAb和基于细胞的ADAM 17重建试验进一步证明了ADAM 17的CD16 b脱落。然而，与人CD16不同，小鼠CD16在中性粒细胞刺激或凋亡后不经历有效的胞外域脱落，表明这种机制不能在正常小鼠中建模。综上所述，我们的研究结果首次直接证明了ADAM 17在人类白细胞中切割CD 16。
CD16b (FcγRIIIb) is exclusively expressed by human neutrophils and binds IgG in immune complexes. Cell surface CD16b undergoes efficient ectodomain shedding upon neutrophil activation and apoptosis. Indeed, soluble CD16b is present at high levels in the plasma of healthy individuals, which appears to be maintained by the daily turnover of apoptotic neutrophils. At this time, the principal protease responsible for CD16b shedding is not known. We show that CD16b plasma levels were significantly decreased in patients administered a selective inhibitor targeting the metalloproteases ADAM10 and ADAM17. Additional analysis with inhibitors selective for ADAM10 or ADAM17 revealed that only inhibition of ADAM17 significantly blocked the cleavage of CD16b following neutrophil activation and apoptosis. CD16b shedding by ADAM17 was further demonstrated using a unique ADAM17 function-blocking mAb and a cell-based ADAM17 reconstitution assay. Unlike human CD16, however, mouse CD16 did not undergo efficient ectodomain shedding upon neutrophil stimulation or apoptosis, indicating that this mechanism cannot be modeled in normal mice. Taken together, our findings are the first to directly demonstrate that ADAM17 cleaves CD16 in human leukocytes.
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影响因子：
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影响因子：
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