Cxcr2 and Cxcl5 regulate the IL-17/G-CSF axis and neutrophil homeostasis in mice
Cxcr2 and Cxcl5 regulate the IL-17/G-CSF axis and neutrophil homeostasis in mice
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DOI：
10.1172/jci60588
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发表时间：
2012-03-01
影响因子：
15.9
通讯作者：
Worthen, G. Scott
中科院分区：
文献类型：
--
作者：
Mei, Junjie;Liu, Yuhong;Worthen, G. Scott
中性粒细胞对于在正常条件下维持先天免疫监视至关重要，但也是炎症期间组织损伤的主要因素。因此，神经元内稳态受到严格调节。Cxcr 2在中性粒细胞稳态中起关键作用，因为Cxcr 2（-/-）小鼠在骨髓中表现出轻度嗜中性粒细胞和重度中性粒细胞增生。然而，这些表型的机制尚不清楚。我们在这里报告说，Cxcr 2对小鼠中性粒细胞抑制IL-17 A/G-CSF轴，调节中性粒细胞的稳态。此外，肠中肠细胞来源的Cxcl 5调节IL-17/G-CSF水平并有助于Cxcr 2依赖性中性粒细胞稳态。相反，中性粒细胞稳态的Cxc 15依赖性调节需要G-CSF，并且IL-17 A的抑制降低了Cxc 15（-/-）和Cxcr 2（-/-）小鼠中的血浆G-CSF浓度和骨髓中性粒细胞数量。Cxcr 2（-/-）小鼠组成型表达IL-17 A，并显示肺、末端回肠和脾脏中产生IL-17 A的细胞数量增加。大多数产生IL-17的脾细胞在体外对IL-1 β加IL-23有反应。在Cxcr 2（-/-）小鼠中通过抗生素治疗消耗肠道微生物显著降低IL-17 A和G-CSF表达、嗜中性粒细胞和骨髓髓样增生。这些数据表明，Cxcr 2，Cxcl 5和肠道细菌在调节IL-17/G-CSF轴和粘膜部位的中性粒细胞稳态中的关键作用，并对开发由过度或无效的中性粒细胞应答引起的病理的治疗具有意义。
Neutrophils are essential for maintaining innate immune surveillance under normal conditions, but also represent a major contributor to tissue damage during inflammation. Neutrophil homeostasis is therefore tightly regulated. Cxcr2 plays a critical role in neutrophil homeostasis, as Cxcr2(-/-) mice demonstrate mild neutrophilia and severe neutrophil hyperplasia in the bone marrow. The mechanisms underlying these phenotypes, however, are unclear. We report here that Cxcr2 on murine neutrophils inhibits the IL-17A/G-CSF axis that regulates neutrophil homeostasis. Furthermore, enterocyte-derived Cxcl5 in the gut regulates IL-17/G-CSF levels and contributes to Cxcr2-dependent neutrophil homeostasis. Conversely, G-CSF was required for Cxcl5-dependent regulation of neutrophil homeostasis, and inhibition of IL-17A reduced plasma G-CSF concentrations and marrow neutrophil numbers in both Cxcl5(-/-) and Cxcr2(-/-) mice. Cxcr2(-/-) mice constitutively expressed IL-17A and showed increased numbers of IL-17A-producing cells in the lung, terminal ileum, and spleen. Most IL-17-producing splenocytes were responsive to IL-1 beta plus IL-23 in vitro. Depletion of commensal microbes by antibiotic treatment in Cxcr2(-/-) mice markedly decreased IL-17A and G-CSF expression, neutrophilia, and marrow myeloid hyperplasia. These data suggest a critical role for Cxcr2, Cxcl5, and commensal bacteria in regulation of the IL-17/G-CSF axis and neutrophil homeostasis at mucosal sites and have implications for the development of treatments for pathologies resulting from either excessive or ineffective neutrophil responses.