CXC Chemokines and Regulation of Granulopoiesis

描述(申请人提供)：趋化因子受体CXCR2是小鼠体内唯一的ELR CXC趋化因子受体，其缺失会增加骨髓中的中性粒细胞和祖细胞，以及系统表达G-CSF和IL-17A。我们的CXCL5-/-小鼠缺乏CXCR2的一个配体，表现出一种中间表型，表明CXCL5参与了通过CXCR2控制粒系生成。此外，这些小鼠对严重肺炎的抵抗力更强。我们的数据表明，IL-17调节这种表型以响应来自环境的信号。根据新的初步数据表明，共生细菌的消融损害了肺宿主防御，我们假设共生细菌诱导肠道中表达IL-17的淋巴样细胞，而这种细胞被CXCL5诱导的中性粒细胞内流所减弱。在中性粒细胞缺乏完全可获得性的情况下，产生IL-17的细胞启动一个诱导粒细胞生成和增强肺宿主防御的系统过程。利用小鼠系统，我们将解决以下特定目标：1.确定CXCR2-/-和CXCL5-/-小鼠的粒细胞增殖是否是由于IL-1/IL-23/IL-17/G-CSF途径的激活，解决IL-17的来源是否在粘膜部位，以及天然淋巴样细胞的作用。2.确定IL-17/G-CSF轴是否介导了CXCL5-/-小鼠增强的肺宿主防御，重点是调节IL-17细胞和中性粒细胞的转运，以及对肺宿主防御基因的修饰。3.确定共生菌在通过IL-17调节宿主防御中的重要性。这些研究将解决关键的悬而未决的问题，即肠道微生物的变化如何改变肺对细菌感染的抵抗力，并提供新的途径来增强宿主抵抗力或减少肺部的中性粒细胞炎症。

DESCRIPTION (provided by applicant): The chemokine receptor CXCR2 is the only receptor for ELR+ CXC chemokines in the mouse, deletion of which increases of neutrophils and progenitors in the marrow, as well as systemic expression of G-CSF and IL-17A. Our CXCL5-/- mice, which lack one ligand for CXCR2, express an intermediate phenotype, suggesting involvement of CXCL5 in controlling granulopoiesis through CXCR2. Furthermore, these mice are more resistant to severe pneumonia. Our data suggest that IL-17 regulates this phenotype in response to signals from the environment. Based on new preliminary data indicating that ablation of commensal bacteria impairs lung host defense, we hypothesize that commensal bacteria induce IL-17-expressing lymphoid cells in the gut that is attenuated by CXCL5- induced influx of neutrophils. In the absence of full neutrophil availability, IL-17- producing cells initite a systemic process inducing granulopoiesis and increasing lung host defense. Using murine systems, we will address the following Specific Aims: 1. Determine whether granulocytic hyperplasia in CXCR2-/- and CXCL5-/- mice is due to activation of an IL-1/IL-23/IL-17/G-CSF pathway, addressing whether the source of IL-17 is at mucosal sites, and the role of innate lymphoid cells. 2. Determine whether the IL- 17/G-CSF axis mediates the enhanced lung host defense seen in CXCL5-/- mice, focusing on regulation of trafficking of IL-17 cells and neutrophils, and modification of lung host defense genes 3. Determine the importance of commensal bacteria in regulating host defense through IL-17. These studies will address critical unanswered questions in how alterations in gut microbes may alter the lung resistance to bacterial infection, and offer new routes to enhance host resistance or decrease neutrophilic inflammation in the lung.