Chemokines play a crucial role in combating microbial infection by recruiting blood neutrophils to infected tissue. In mice, the chemokines Cxcl1/KC and Cxcl2/MIP2 fulfill this role. Cxcl1 and Cxcl2 exist as monomers and dimers, and exert their function by activating the Cxcr2 receptor and binding glycosaminoglycans (GAGs). Here, we characterized Cxcr2 G protein and β‐arrestin activities, and GAG heparan sulfate (HS) interactions of Cxcl1 and Cxcl2 and of the trapped dimeric variants. To understand how Cxcr2 and GAG interactions impact in vivo function, we characterized their neutrophil recruitment activity to the peritoneum, Cxcr2 and CD11b levels on peritoneal and blood neutrophils, and transport profiles out of the peritoneum. Cxcl2 variants compared with Cxcl1 variants were more potent for Cxcr2 activity. Native Cxcl1 compared with native Cxcl2 and dimers compared with native proteins bound HS with higher affinity. Interestingly, recruitment activity between native Cxcl1 and Cxcl2, between dimers, and between the native protein and the dimer could be similar or very different depending on the dose or the time point. These data indicate that peritoneal neutrophil recruitment cannot be solely attributed to Cxcr2 or GAG interactions, and that the relationship between recruited neutrophils, Cxcr2 activation, GAG interactions, and chemokine levels is complex and highly context dependent. We propose that the ability of Cxcl1 and Cxcl2 to reversibly exist as monomers and dimers and differences in their Cxcr2 activity and GAG interactions coordinate neutrophil recruitment and activation, which play a critical role for successful resolution of inflammation.

中文翻译：

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趋化因子 Cxcl1/KC 和 Cxcl2/MIP2 募集中性粒细胞：Cxcr2 激活和糖胺聚糖相互作用的作用

趋化因子通过将血液中性粒细胞募集到受感染的组织来对抗微生物感染，发挥着至关重要的作用。在小鼠中，趋化因子 Cxcl1/KC 和 Cxcl2/MIP2 发挥着这一作用。Cxcl1 和 Cxcl2 以单体和二聚体形式存在，通过激活 Cxcr2 受体并结合糖胺聚糖 (GAG) 发挥其功能。在这里，我们表征了 Cxcr2 G 蛋白和 β-arrestin 活性，以及​​ Cxcl1 和 Cxcl2 以及捕获的二聚体变体的 GAG 硫酸乙酰肝素 (HS) 相互作用。为了了解 Cxcr2 和 GAG 相互作用如何影响体内功能，我们表征了它们向腹膜的中性粒细胞募集活性、腹膜和血液中性粒细胞的 Cxcr2 和 CD11b 水平以及腹膜外的转运特征。与 Cxcl1 变体相比，Cxcl2 变体对 Cxcr2 活性更有效。天然 Cxcl1 与天然 Cxcl2 相比，二聚体与天然蛋白相比，以更高的亲和力结合 HS。有趣的是，天然 Cxcl1 和 Cxcl2 之间、二聚体之间以及天然蛋白和二聚体之间的招募活性可能相似或非常不同，具体取决于剂量或时间点。这些数据表明腹膜中性粒细胞募集不能仅仅归因于 Cxcr2 或 GAG 相互作用，并且募集的中性粒细胞、Cxcr2 激活、GAG 相互作用和趋化因子水平之间的关系是复杂的且高度依赖于环境。我们认为，Cxcl1 和 Cxcl2 作为单体和二聚体可逆存在的能力以及它们的 Cxcr2 活性和 GAG 相互作用的差异协调中性粒细胞的募集和激活，这对于成功解决炎症起着关键作用。