CXCL9 inhibits eosinophil responses by a CCR3- and Rac2-dependent mechanism
CXCL9 inhibits eosinophil responses by a CCR3- and Rac2-dependent mechanism
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DOI：
10.1182/blood-2005-02-0489
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发表时间：
2005-07-15
期刊：
影响因子：
20.3
通讯作者：
Rothenberg, ME
中科院分区：
文献类型：
--
作者：
Fulkerson, PC;Zhu, HY;Rothenberg, ME
最近，抑制白细胞趋化和激活的细胞因子途径已被发现，但除了依赖于简单受体拮抗的模型外，对其作用机制还缺乏深入的了解。我们以前已经发现存在由CXC趋化因子配体9(CXCL9，Mig[干扰素-γ诱导的单核因子])介导的小鼠嗜酸粒细胞抑制通路，该通路可以显著地阻断嗜酸性粒细胞的趋化作用和功能，但其机制仍不清楚。我们现在证明Mig的抑制作用不仅仅是受体拮抗作用。值得注意的是，除了抑制嗜酸粒细胞趋化因子诱导的丝状肌动蛋白(F-肌动蛋白)的形成和化学吸引外，Mig还有效地阻断了血小板激活因子(PAF)和白三烯B4(LTB4)诱导的反应。值得注意的是，在没有激动剂刺激的情况下，经Mig处理的嗜酸性粒细胞表现出异常的F-肌动蛋白组装。此外，Mig预处理可抑制嗜酸性粒细胞三磷酸酶(GTPase)RAC的激活，而缺乏Rac2的嗜酸性粒细胞对Eoaxin刺激的迁移和肌动蛋白聚合反应减弱。此外，Mig不能抑制嗜酸性粒细胞嗜酸性粒细胞对嗜酸性粒细胞嗜酸性粒细胞的嗜酸性粒细胞趋化反应。最后，利用CCR3基因靶向的细胞，Mig的抑制活性被证明是由CC趋化因子受体3(CCR3)介导的。因此，通过改变激动剂诱导的信号转导和通过依赖于rac2的机制消除细胞骨架重组，Mig显著抑制嗜酸性粒细胞对不同刺激的反应。这些结果证实了不同的趋化因子可以使用CCR3在嗜酸性粒细胞中诱导相反的信号。
Recently, inhibitory cytokine pathways for leukocyte chemoattraction and activation have been identified, but there is little insight into the operational mechanisms except for models that rely on simple receptor antagonism. We have previously identified the existence of a murine eosinophil inhibitory pathway mediated by the CXC chemokine ligand 9 (CXCL9, Mig [monokine induced by interferon-gamma]) that impressively blocks eosinophil chemoattraction and function, but the mechanism has remained elusive. We now demonstrate that Mig's inhibitory action extends beyond receptor antagonism alone. Notably, in addition to inhibiting eotaxin-induced filamentous actin (F-actin) formation and chemoattraction, Mig potently blocks platelet activating factor (PAF)and leukotriene B4 (LTB4)-induced responses. Remarkably, Mig-treated eosinophils display an abnormal F-actin assembly in the absence of agonist stimulation. Additionally, Mig pretreatment inhibits eotaxin-induced activation of the Rhoguanosine triphosphatase (GTPase) Rac, and Rac2-deficient eosinophils demonstrate an impaired transmigration and actin polymerization response to eotaxin stimulation. Furthermore, Mig was unable to inhibit eotaxin-induced responses in Rac2-deficient eosinophils. Finally, using CCR3 gene-targeted cells, Mig's inhibitory activity is demonstrated to be mediated by CC chemokine receptor 3 (CCR3). Thus, by altering agonist-induced signaling and abrogating cytoskeletal reorganization by a Rac2-dependent mechanism, Mig markedly inhibits eosinophil responses to diverse stimuli. These results establish evidence that distinct chemokines can use CCR3 to induce opposing signals in eosinophils.