Monomeric and dimeric CXCL8 are both essential for in vivo neutrophil recruitment.
Monomeric and dimeric CXCL8 are both essential for in vivo neutrophil recruitment.
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DOI：
10.1371/journal.pone.0011754
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发表时间：
2010-07-26
期刊：
影响因子：
3.7
通讯作者：
Rajarathnam K
中科院分区：
文献类型：
--
作者：
Das ST;Rajagopalan L;Guerrero-Plata A;Sai J;Richmond A;Garofalo RP;Rajarathnam K
中性粒细胞从脉管系统快速动员到细菌/病毒感染和组织损伤部位是成功解决炎症的关键步骤。趋化因子 CXCL8 在招募中性粒细胞中发挥着核心作用。 CXCL8的一个特征是它能够以单体和二聚体可逆地存在，但是这两种形式是否存在于体内，如果存在，每种形式与体内功能的相关性尚不清楚。在这项研究中，使用“捕获的”非缔合单体和非解离二聚体，我们表明（i）野生型（WT）CXCL8同时以单体和二聚体形式存在，（ii）单体、二聚体和WT的体内招募概况明显不同，（iii）二聚体对于初始稳健招募至关重要，而WT对于持续招募最活跃。使用微流体装置，我们还观察到募集不仅取决于CXCL8的总量，还取决于梯度的陡度，并且不同CXCL8变体产生的梯度引起不同的中性粒细胞迁移反应。 CXCL8 通过与中性粒细胞上的 CXCR2 受体和内皮细胞上的糖胺聚糖 (GAG) 结合来介导其功能。根据我们的数据，我们提出CXCL8单体和二聚体之间的动态平衡及其与CXCR2和GAG的差异结合介导和调节体内中性粒细胞募集。我们发现 CXCL8 单体和二聚体在体内均具有功能，这一发现是新颖的，这表明 CXCL8 单体-二聚体平衡和中性粒细胞募集与健康和疾病密切相关。
Rapid mobilization of neutrophils from vasculature to the site of bacterial/viral infections and tissue injury is a critical step in successful resolution of inflammation. The chemokine CXCL8 plays a central role in recruiting neutrophils. A characteristic feature of CXCL8 is its ability to reversibly exist as both monomers and dimers, but whether both forms exist in vivo, and if so, the relevance of each form for in vivo function is not known. In this study, using a ‘trapped’ non-associating monomer and a non-dissociating dimer, we show that (i) wild type (WT) CXCL8 exists as both monomers and dimers, (ii) the in vivo recruitment profiles of the monomer, dimer, and WT are distinctly different, and (iii) the dimer is essential for initial robust recruitment and the WT is most active for sustained recruitment. Using a microfluidic device, we also observe that recruitment is not only dependent on the total amount of CXCL8 but also on the steepness of the gradient, and the gradients created by different CXCL8 variants elicit different neutrophil migratory responses. CXCL8 mediates its function by binding to CXCR2 receptor on neutrophils and glycosaminoglycans (GAGs) on endothelial cells. On the basis of our data, we propose that dynamic equilibrium between CXCL8 monomers and dimers and their differential binding to CXCR2 and GAGs mediates and regulates in vivo neutrophil recruitment. Our finding that both CXCL8 monomer and dimer are functional in vivo is novel, and indicates that the CXCL8 monomer-dimer equilibrium and neutrophil recruitment are intimately linked in health and disease.
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