1Respiratory Research Division, Department of Medicine, Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland.
J Clin Invest. 2010 Dec;120(12):4236-50. doi: 10.1172/JCI41196. Epub 2010 Nov 8.
Hereditary deficiency of the protein α-1 antitrypsin (AAT) causes a chronic lung disease in humans that is characterized by excessive mobilization of neutrophils into the lung. However, the reason for the increased neutrophil burden has not been fully elucidated. In this study we have demonstrated using human neutrophils that serum AAT coordinates both CXCR1- and soluble immune complex (sIC) receptor-mediated chemotaxis by divergent pathways. We demonstrated that glycosylated AAT can bind to IL-8 (a ligand for CXCR1) and that AAT-IL-8 complex formation prevented IL-8 interaction with CXCR1. Second, AAT modulated neutrophil chemotaxis in response to sIC by controlling membrane expression of the glycosylphosphatidylinositol-anchored (GPI-anchored) Fc receptor FcγRIIIb. This process was mediated through inhibition of ADAM-17 enzymatic activity. Neutrophils isolated from clinically stable AAT-deficient patients were characterized by low membrane expression of FcγRIIIb and increased chemotaxis in response to IL-8 and sIC. Treatment of AAT-deficient individuals with AAT augmentation therapy resulted in increased AAT binding to IL-8, increased AAT binding to the neutrophil membrane, decreased FcγRIIIb release from the neutrophil membrane, and normalization of chemotaxis. These results provide new insight into the mechanism underlying the effect of AAT augmentation therapy in the pulmonary disease associated with AAT deficiency.
遗传性α-1 抗胰蛋白酶（AAT）缺乏会导致人类慢性肺部疾病，其特征是中性粒细胞过度向肺部迁移。然而，导致中性粒细胞负担增加的原因尚未完全阐明。在这项研究中，我们使用人中性粒细胞证明，血清 AAT 通过不同的途径协调 CXCR1 和可溶性免疫复合物（sIC）受体介导的趋化作用。我们证明糖基化 AAT 可以与 CXCR1 的配体 IL-8 结合，并且 AAT-IL-8 复合物的形成阻止了 IL-8 与 CXCR1 的相互作用。其次，AAT 通过控制糖基磷脂酰肌醇锚定（GPI-锚定）Fc 受体 FcγRIIIb 的膜表达来调节对 sIC 的中性粒细胞趋化作用。这个过程是通过抑制 ADAM-17 酶活性来介导的。从临床稳定的 AAT 缺乏症患者中分离出的中性粒细胞的特征是 FcγRIIIb 膜表达降低，并且对 IL-8 和 sIC 的趋化性增加。用 AAT 增强疗法治疗 AAT 缺乏症个体导致 AAT 与 IL-8 的结合增加，AAT 与中性粒细胞膜的结合增加，FcγRIIIb 从中性粒细胞膜上的释放减少，以及趋化性正常化。这些结果为 AAT 增强疗法在与 AAT 缺乏相关的肺部疾病中的作用机制提供了新的见解。
