CXC Chemokines and Regulation of Granulopoiesis

CXC趋化因子和粒细胞生成的调节

• 批准号: 8636398
• 负责人: George SCOTT WORTHEN
• 金额: $ 41.88万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-15 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8636398
• 关键词: Ablation; Address; Apoptotic; Attenuated; Bacteria; Bacterial Infections; Bacterial Pneumonia; CSF3 gene; CXC Chemokines; CXCL5 gene; Cells; Data; Environment; Epithelial Cells; Feedback; Gene Expression; Genes; Granulopoiesis; Host Defense; Host resistance; Hyperplasia; IL8RB gene; Inflammation; Inflammatory; Interleukin-1; Interleukin-17; Intestines; Ligands; Lung; Lung diseases; Lymphocyte; Lymphoid; Lymphoid Cell; Marrow; Mediating; Microbe; Modeling; Modification; Mus; Organ; Pathway interactions; Phagocytes; Phagocytosis; Phenotype; Pneumonia; Process; Production; Recruitment Activity; Regulation; Resistance; Role; Route; Sentinel; Severities; Signal Transduction; Site; Source; Stimulus; Surface; System; Testing; Tissues; antimicrobial; bacterial resistance; base; chemokine receptor; commensal microbes; improved; interleukin-23; macrophage; microbiome; mucosal site; neutrophil; novel strategies; pathogen; progenitor; public health relevance; receptor; response; trafficking

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.

描述（由申请人提供）：趋化因子受体CXCR 2是小鼠中ELR+ CXC趋化因子的唯一受体，其缺失增加骨髓中的嗜中性粒细胞和祖细胞，以及G-CSF和IL-17 A的全身表达。我们的CXCL 5-/-小鼠，缺乏一个CXCR 2配体，表达一个中间表型，表明CXCL 5通过CXCR 2参与控制粒细胞生成。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调节这种表型响应于来自环境的信号。根据新的初步数据表明，消融的大肠杆菌损害肺宿主的防御，我们假设大肠杆菌诱导IL-17表达的淋巴细胞在肠道中，这是减弱CXCL 5诱导的中性粒细胞的流入。在没有完全中性粒细胞可用性的情况下，IL-17产生细胞启动诱导粒细胞生成和增加肺宿主防御的系统过程。使用鼠系统，我们将解决以下具体目标：1。确定CXCR 2-/-和CXCL 5-/-小鼠中的粒细胞增生是否是由于IL-1/IL-23/IL-17/G-CSF通路的激活，说明IL-17的来源是否在粘膜部位，以及先天性淋巴细胞的作用。2.确定IL- 17/G-CSF轴是否介导CXCL 5-/-小鼠中观察到的增强的肺宿主防御，重点关注IL-17细胞和中性粒细胞的运输调节以及肺宿主防御基因的修饰3。确定肠道细菌通过IL-17调节宿主防御的重要性。这些研究将解决肠道微生物的改变如何改变肺部对细菌感染的抵抗力的关键未回答的问题，并提供新的途径来增强宿主抵抗力或减少肺部嗜酸性炎症。