Recruitment of CX3CR1-GFP+ monocytes during Schistosoma mansoni infection.

曼氏血吸虫感染期间 CX3CR1-GFP 单核细胞的募集。

• 批准号: 8223147
• 负责人: Png Loke
• 金额: $ 21.13万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-15 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8223147
• 关键词: Acute; Adopted; Affect; Allergic Reaction; Area; Attention; Bacterial Infections; Behavior; Blood; Blood Vessels; CD4 Positive T Lymphocytes; CX3CL1 gene; Cell physiology; Cells; Characteristics; Chronic; Chronic Disease; Confocal Microscopy; Congenic Mice; Flow Cytometry; Goals; Granuloma; Helminths; Hepatic Granuloma; Homeostasis; Image; Imagery; Immune; Immunity; Infection; Inflammation; Inflammatory; Injury; Integrin Binding; Interleukin-4; Intervention; Measurement; Measures; Membrane; Microscopy; Modeling; Mus; Myocardial Infarction; Normal tissue morphology; Parasites; Pathway interactions; Phenotype; Play; Population; Process; Property; Recruitment Activity; Regulation; Reporter; Research; Resolution; Role; STAT6 gene; Schistosoma; Schistosoma mansoni; Schistosoma mansonii infection; Signal Transduction; Sorting - Cell Movement; Staging; Sterility; T-Lymphocyte; Testing; Th2 Cells; Time; Tissues; Wound Healing; base; cell type; design; egg; immunopathology; immunoregulation; improved; in vivo; intravital microscopy; macrophage; monocyte; pathogen; public health relevance; response; trafficking

DESCRIPTION (provided by applicant): Macrophages (MF) are essential for immunity against pathogens, tissue homeostasis and immune regulation. Helminth infections, allergic reactions and tissue injury can induce the differentiation of alternatively activated macrophages (AAMF), which are important in promoting tissue remodeling, wound repair, T helper 2 (TH2) differentiation and parasite clearance. The differentiation process and cellular precursors of AAMF remains poorly understood. Recently, two functionally distinct subsets of monocytes and their properties have been described; (1) Ly-6C+ "inflammatory" monocytes and (2) Ly6C- "resident" monocytes. While Ly6C- monocytes populate normal tissues, they have also been shown to patrol blood vessels and extravasate rapidly into inflamed or infected tissues to promote the resolution of inflammation. Ly6C- cells are also CX3CR1-GFPhi in a CX3CR1-GFP reporter mouse and have been best characterized in models of myocardial infarction and bacterial infection. In both models, extravasated Ly6C-, CX3CR1-GFPhi monocytes have characteristics of AAMF and can promote tissue remodeling, wound healing and immune modulation. We have previously shown that helminth infection potently induces recruitment of AAMF. Others have shown that the recruitment of AAMF is critical in protecting S. mansoni infected mice from acute immunopathology in response to the eggs. We have also recently shown that sterile tissue injury can induce recruitment of AAMF in the absence of infection, through a T cell independent innate immune pathway. We have now conducted preliminary flow cytometry, confocal microscopy and intra-vital imaging studies of the liver granulomas of S. mansoni infected CX3CR1-GFP/+ mice, which suggest that AAMF are CX3CR1-GFPhi and may arise from the Ly6C-, CX3CR1-GFPhi monocytes that are patrolling the sinusoidal vessels. In this proposal, we propose to use intra-vital microscopy to observe T cell-macrophage interactions in the liver granulomas of S. mansoni infected mice. Specifically, we propose to test the hypothesis that AAMF recruited by S. mansoni eggs differentiate from CX3CR1-GFPhi, Ly6C- monocytes. As a secondary hypothesis, we propose that CD4+ T cells may play a role in recruiting or maintaining CX3CR1-GFP+ cells into the granulomas to differentiate into AAMF during chronic infection. Therefore, our specific aims are: (1) to visualize the dynamics of monocyte recruitment and macrophage differentiation in liver granulomas using the CX3CR1- GFP reporter mice; (2) to determine the role of CD4+ TH2 cells in the recruitment of CX3CR1-GFPhi cells by S. mansoni eggs in the liver granulomas. These studies will improve our understanding of monocyte recruitment and macrophage differentiation under Th2 conditions and may provide us with a framework for new interventional therapies to regulate pathogenic inflammatory Th2 responses. PUBLIC HEALTH RELEVANCE: Macrophages activated under T helper type 2 conditions are important in wound healing, allergic reactions and parasite infections. How these cells are recruited into the tissues from monocytes in the blood is not clear. The goal of this project is to identify where these macrophages come from in order to design interventional strategies that could help regulate the inflammatory process during a type 2 response.

描述（由申请人提供）：巨噬细胞（MF）对于防止病原体，组织稳态和免疫调节的免疫力至关重要。蠕虫感染，过敏反应和组织损伤可以引起替代激活的巨噬细胞（AAMF）的分化，这对于促进组织重塑，伤口修复，T辅助2（TH2）分化和寄生虫清除很重要。 AAMF的分化过程和细胞前体仍然了解不足。最近，已经描述了两个在功能上不同的单核细胞及其特性的子集。 （1）LY-6C+“炎症”单核细胞和（2）Ly6c-“居民”单核细胞。虽然Ly6c-单核细胞填充了正常组织，但它们还被证明会巡逻血管并迅速扩展到发炎或感染的组织中，以促进炎症的分辨率。 LY6C-细胞也是CX3CR1-GFP报告基因小鼠中的CX3CR1-GFPHI，并且在心肌梗塞和细菌感染模型中的表征最佳。在这两种模型中，CX3CR1-GFPHI单核细胞具有AAMF的特征，可以促进组织重塑，伤口愈合和免疫调节。 我们以前已经表明，蠕虫感染有效地诱导了AAMF的募集。其他人则表明，AAMF的募集对于保护曼氏链球菌感染的小鼠免受急性免疫病理的反应至关重要。我们最近还表明，无菌组织损伤可以在没有感染的情况下通过T细胞独立的先天免疫途径诱导AAMF募集。现在，我们对曼氏链球菌感染的CX3CR1-GFP/+小鼠的肝肉芽肿研究进行了初步流式细胞仪，共聚焦显微镜和重要的成像研究，这表明AAMF是CX3CR1-GFPHI，并且可能是由ly6c-，cx3cr1-gfphi monocal patheral patter the and canterall patheraty patheraty patheraty patheraty patheraty patheraty patheration patheraty patheraty patheraty patheraty。 在此提案中，我们建议使用重要的内显微镜观察曼氏链球菌感染小鼠的肝脏肉芽肿中的T细胞巨噬细胞相互作用。具体而言，我们建议检验以下假设：曼氏链球菌与CX3CR1-GFPHI（LY6C-单核细胞）区分开的AAMF。作为次要假设，我们建议CD4+ T细胞可能在募集或维持CX3CR1-GFP+细胞中发挥作用，以在慢性感染期间分化为AAMF。因此，我们的具体目的是：（1）使用CX3CR1- GFP报告基因小鼠可视化肝肉芽肿的单核细胞募集和巨噬细胞分化的动力学； （2）确定CD4+ Th2细胞在肝脏肉芽肿中通过S. mansoni卵在募集CX3CR1-GFPHI细胞中的作用。这些研究将提高我们对TH2条件下单核细胞募集和巨噬细胞分化的理解，并可能为我们提供新的介入疗法的框架，以调节致病性TH2反应。 公共卫生相关性：在T型辅助2型条件下激活的巨噬细胞在伤口愈合，过敏反应和寄生虫感染中很重要。这些细胞如何从血液中的单核细胞中募集到组织中尚不清楚。该项目的目的是确定这些巨噬细胞的来源，以设计介入的策略，以帮助调节2型响应期间的炎症过程。