Regulation of CXCR2 expression and function by a disintegrin and metalloprotease-17 (ADAM17)
Regulation of CXCR2 expression and function by a disintegrin and metalloprotease-17 (ADAM17)
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DOI：
10.1189/jlb.3hi0714-340r
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发表时间：
2015-03-01
影响因子：
5.5
通讯作者：
Walcheck, Bruce
中科院分区：
文献类型：
--
作者：
Mishra, Hemant K.;Long, Chunmei;Walcheck, Bruce
趋化因子受体CXCR 2在循环中性粒细胞上以高水平表达，并且对于引导它们迁移到炎症部位至关重要。CXCR 2表面水平被2种机制--细胞内化和配体结合后的再循环--以及非配体刺激引起的中性粒细胞明显活化后的金属蛋白酶活性快速调节。后一个过程仅在人类中性粒细胞中描述过，基本上，对其功能相关性和所涉及的特异性蛋白酶一无所知。我们发现，在小鼠和人类中性粒细胞中靶向ADAM 17阻断了由非配体刺激诱导的CXCR 2下调，但不阻断趋化因子配体诱导的CXCR 2下调。这是通过使用选择性ADAM 17抑制剂、ADAM 17功能阻断抗体和ADAM 17基因靶向小鼠来确定的。已知CXCR 2在各种炎症性疾病期间经历显著下调，并且这与受损的中性粒细胞募集相关。我们发现，阻断ADAM 17活性减少了CXCR 2对循环中性粒细胞的下调，并在急性炎症期间增加了它们的募集，这被CXCR 2抑制剂逆转。总之，我们的研究结果表明，与CXCR 2内化不同，ADAM 17诱导以不可逆的方式下调受体，并可能作为控制CXCR 2功能的主开关，但也可能导致过度炎症期间中性粒细胞功能障碍。
The chemokine receptor CXCR2 is expressed at high levels on circulating neutrophils and is critical for directing their migration to sites of inflammation. CXCR2 surface levels are rapidly modulated by 2 mechanisms-cell internalization and recycling upon ligand binding-and by a metalloprotease activity following overt neutrophil activation by nonligand stimuli. The latter process has only been described in human neutrophils, and essentially, nothing is known about its functional relevance and the specific protease involved. We show that targeting ADAM17 in mouse and human neutrophils blocks CXCR2 down-regulation induced by nonligand stimuli but not by chemokine ligands. This was determined by use of a selective ADAM17 inhibitor, an ADAM17 function-blocking antibody, and ADAM17 gene-targeted mice. CXCR2 is known to undergo a marked down-regulation during various inflammatory disorders, and this is associated with impaired neutrophil recruitment. We show that blocking ADAM17 activity reduced CXCR2 down-regulation on circulating neutrophils and enhanced their recruitment during acute inflammation, which was reversed by a CXCR2 inhibitor. Taken together, our findings demonstrate that unlike CXCR2 internalization, ADAM17 induction down-regulates the receptor in an irreversible manner and may serve as a master switch in controlling CXCR2 function, but may also contribute to neutrophil dysfunction during excessive inflammation.