Regulation of monocyte recruitment and function by the IL-23/IL-17 axis

IL-23/IL-17 轴对单核细胞募集和功能的调节

• 批准号: 8284851
• 负责人: RANCE E BERG
• 金额: $ 7.25万
• 依托单位: UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-07 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8284851
• 关键词: Address; Allergic Disease; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Bacteria; Biological Assay; Blood; Blood Circulation; Bone Marrow; CCL2 gene; CCL7 gene; Cancerous; Cell physiology; Cells; Containment; Data; Dendritic Cells; Disease; Emigrations; Family member; Generations; Grant; Immune; Immunocompromised Host; In Vitro; Individual; Infection; Inflammation; Inflammatory; Interleukin-12; Interleukin-17; Knowledge; Lead; Listeria monocytogenes; Liver; Maintenance; Malignant Neoplasms; Measures; Mediating; Meningitis; Mus; Myeloid Cells; Natural Immunity; Neoplasm Metastasis; Neutrophil Infiltration; Nitric Oxide; Phagocytes; Predisposition; Pregnant Women; Production; Publishing; Recruitment Activity; Regulation; Septicemia; Site; Spleen; Spontaneous abortion; Systemic infection; TNF gene; Therapeutic; Tissues; Translational Research; Up-Regulation; Vaccines; bactericide; base; cell type; chemokine; cytokine; in vivo; interleukin-22; interleukin-23; macrophage; monocyte; neutrophil; novel; pathogen; peripheral blood; receptor; research study; secondary infection; tumor

DESCRIPTION (provided by applicant): Listeria monocytogenes (LM) is an intracellular bacterium that can cause spontaneous abortions in pregnant women and can lead to septicemia and meningitis in immunocompromised individuals. Innate immunity to LM and other pathogens is provided by neutrophils, monocytes and macrophages. Monocytes are bone marrow derived myeloid cells that circulate in the peripheral blood until being mobilized into tissues. Resident monocytes give rise to tissue macrophages and dendritic cells, while inflammatory monocytes provide protection against infections but can also be detrimental during cancer and other autoimmune/inflammatory diseases. Our published data have revealed that the cytokine IL-23 and the receptor for IL-17A and IL-17F (IL- 17RA) are required for protection against LM infection. We have now established that IL-23 is required for optimal monocyte recruitment during LM infection. Based upon these published data and our novel observations, we hypothesize that the IL-23/IL-17 axis regulates the recruitment and function of monocytes during systemic LM infection. A variety of in vivo and in vitro approaches utilizing mice lacking IL-23, IL-17RA, IL-17A, and IL-17F will specifically address the following aims. Specific Aim 1 will determine how the IL-23/IL-17 axis regulates monocyte recruitment during LM infection. Mice lacking IL-23, IL-17RA, IL- 17A, and IL-17F will be utilized to determine how these molecules influence monocyte recruitment before, and during, LM infection. Furthermore, the direct and indirect impact of these cytokines on monocyte recruiting chemokines will be determined. Specific Aim 2 will determine how the IL-23/IL-17 axis enhances monocyte function during LM infection. The requirement and sufficiency of the IL-23/IL-17 axis for optimal monocyte effector functions will be determined by measuring monocyte effector molecules that are required for protection against LM. The data obtained from these studies may lead to therapeutic options aimed at regulating monocyte function during infectious and other disease states. PUBLIC HEALTH RELEVANCE: Data generated upon completion of this proposal will result in a detailed understanding of how cytokines (IL- 23/IL-17) regulate the function of monocytes during systemic infection. This knowledge will allow for more effective vaccine generation and lead to strategies to either enhance or limit monocyte function during different disease states including cancer, autoimmunity, and infection.

描述（由申请人提供）：单核细胞增生李斯特氏菌（LM）是一种细胞内细菌，可导致孕妇自然流产，并可导致免疫功能低下个体的败血症和脑膜炎。对LM和其他病原体的先天免疫是由中性粒细胞、单核细胞和巨噬细胞提供的。单核细胞是骨髓来源的骨髓细胞，在外周血中循环直至动员到组织中。常驻单核细胞产生组织巨噬细胞和树突状细胞，而炎性单核细胞提供针对感染的保护，但在癌症和其他自身免疫/炎性疾病期间也可能是有害的。我们发表的数据表明，细胞因子 IL-23 以及 IL-17A 和 IL-17F 受体 (IL-17RA) 是防止 LM 感染所必需的。我们现在已经确定，在 LM 感染期间，IL-23 是最佳单核细胞募集所必需的。根据这些已发表的数据和我们的新观察，我们假设 IL-23/IL-17 轴在全身性 LM 感染期间调节单核细胞的募集和功能。利用缺乏 IL-23、IL-17RA、IL-17A 和 IL-17F 的小鼠的各种体内和体外方法将具体解决以下目标。具体目标 1 将确定 IL-23/IL-17 轴如何在 LM 感染期间调节单核细胞募集。缺乏IL-23、IL-17RA、IL-17A和IL-17F的小鼠将被用来确定这些分子如何影响LM感染之前和期间的单核细胞募集。此外，还将确定这些细胞因子对单核细胞募集趋化因子的直接和间接影响。具体目标 2 将确定 IL-23/IL-17 轴如何在 LM 感染期间增强单核细胞功能。 IL-23/IL-17 轴对于最佳单核细胞效应功能的需求和充分性将通过测量防止 LM 所需的单核细胞效应分子来确定。从这些研究中获得的数据可能会导致针对在感染和其他疾病状态下调节单核细胞功能的治疗选择。 公共卫生相关性：完成本提案后生成的数据将有助于详细了解细胞因子 (IL-23/IL-17) 在全身感染期间如何调节单核细胞的功能。这些知识将有助于更有效地生产疫苗，并制定在癌症、自身免疫和感染等不同疾病状态下增强或限制单核细胞功能的策略。