IL-6 regulates neutrophil trafficking during acute inflammation via STAT3
IL-6 regulates neutrophil trafficking during acute inflammation via STAT3
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DOI：
10.4049/jimmunol.181.3.2189
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发表时间：
2008-08-01
影响因子：
4.4
通讯作者：
Jenkins, Brendan J.
中科院分区：
文献类型：
--
作者：
Fielding, Ceri A.;McLoughlin, Rachel M.;Jenkins, Brendan J.
炎症的成功解决取决于从最初的中性粒细胞募集到更持续的单核细胞群的协调转变。 IL-6 通过共同受体亚基 gp130 发出信号，通过协调趋化因子的产生和白细胞凋亡，代表炎症反应期间中性粒细胞运输的关键检查点调节剂。然而，特定 IL-6 依赖性信号通路对这些过程的相对贡献仍未解决。为了定义负责 IL-6 驱动的中性粒细胞运输的受体介导的信号传导事件，我们使用了一系列 gp130 敲入突变小鼠，这些小鼠在急性腹膜炎症的实验模型中显示出改变的 IL-6 信号传导能力。 gp(130Y757F/Y757F) 小鼠中 STAT1 和 STAT3 的过度激活导致中性粒细胞的清除速度更快，这与中性粒细胞吸引趋化因子 CXCL1/KC 产生的显着下调相一致。相比之下，炎症浸润中凋亡中性粒细胞的比例不受影响。在缺乏 IL-6 的 gp130(Y757F/Y757F) 小鼠中，中性粒细胞运输和 CXCL1/KC 水平正常，这与 STATI/3 活性水平的降低相对应。此外，gp130(Y757F/V757F)小鼠中Stat3的单等位基因消除特异性降低了STAT3活性，并纠正了中性粒细胞的快速清除和CXCL1/KC产生受损。相反，gp130(Y757F/Y757F) 小鼠中 Stat1 的基因删除未能挽救 gp130(Y757F/U757F) 小鼠中观察到的反应改变。总的来说，这些数据从遗传学上定义了通过 STAT3（而非 STAT1）驱动的 IL-6 信号传导限制了中性粒细胞的炎症募集，因此代表了先天免疫反应终止的关键事件。
The successful resolution of inflammation is dependent upon the coordinated transition from the initial recruitment of neutrophils to a more sustained population of mononuclear cells. IL-6, which signals via the common receptor subunit gp130, represents a crucial checkpoint regulator of neutrophil trafficking during the inflammatory response by orchestrating chemokine production and leukocyte apoptosis. However, the relative contribution of specific IL-6-dependent signaling pathways to these processes remains unresolved. To define the receptor-mediated signaling events responsible for IL-6-driven neutrophil trafficking, we used a series of gp130 knockin mutant mice displaying altered IL-6-signaling capacities in an experimental model of acute peritoneal inflammation. Hyperactivation of STAT1 and STAT3 in gp(130Y757F/Y757F) mice led to a more rapid clearance of neutrophils, and this coincided with a pronounced down-modulation in production of the neutrophil-attracting chemokine CXCL1/KC. By contrast, the proportion of apoptotic neutrophils in the inflammatory infiltrate remained unaffected. In gp130(Y757F/Y757F) mice lacking IL-6, neutrophil trafficking and CXCL1/KC levels were normal, and this corresponded with a reduction in the level of STATI/3 activity. Furthermore, monoallelic ablation of Stat3 in gp130(Y757F/V757F) mice specifically reduced STAT3 activity and corrected both the rapid clearance of neutrophils and impaired CXCL1/KC production. Conversely, genetic deletion of Stat1 in gp130(Y757F/Y757F) mice failed to rescue the altered responses observed in gp130(Y757F/U757F) mice. Collectively, these data genetically define that IL-6-driven signaling via STAT3, but not STAT1, limits the inflammatory recruitment of neutrophils, and therefore represents a critical event for the termination of the innate immune response.