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: 8096081
• 负责人: Png Loke
• 金额: $ 25.35万
• 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 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8096081
• 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; 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）对于病原体免疫、组织稳态和免疫调节至关重要。蠕虫感染、过敏反应和组织损伤可诱导替代活化巨噬细胞 (AAMF) 的分化，这对于促进组织重塑、伤口修复、辅助性 T 2 (TH2) 分化和寄生虫清除非常重要。 AAMF 的分化过程和细胞前体仍然知之甚少。最近，已经描述了两个功能不同的单核细胞亚群及其特性； (1) Ly-6C+“炎性”单核细胞和 (2) Ly6C-“常驻”单核细胞。虽然 Ly6C-单核细胞存在于正常组织中，但它们也被证明可以巡逻血管并迅速外渗到发炎或感染的组织中，以促进炎症的消退。 Ly6C-细胞在CX3CR1-GFP报告小鼠中也是CX3CR1-GFPhi，并且在心肌梗塞和细菌感染模型中得到了最好的表征。在这两种模型中，外渗的Ly6C-、CX3CR1-GFPhi单核细胞均具有AAMF的特征，可以促进组织重塑、伤口愈合和免疫调节。 我们之前已经表明，蠕虫感染可有效诱导 AAMF 的募集。其他人已经表明，AAMF 的募集对于保护曼氏沙门氏菌感染的小鼠免受卵引起的急性免疫病理学至关重要。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 的募集。我们现在对曼氏沙门氏菌感染的CX3CR1-GFP/+小鼠的肝脏肉芽肿进行了初步的流式细胞术、共聚焦显微镜和活体成像研究，表明AAMF是CX3CR1-GFPhi并且可能来自Ly6C-、CX3CR1-正在正弦血管巡逻的 GFPhi 单核细胞。 在本提案中，我们建议使用活体显微镜观察曼氏沙门氏菌感染小鼠肝脏肉芽肿中 T 细胞-巨噬细胞的相互作用。具体来说，我们建议测试以下假设：曼氏酵母卵招募的AAMF与CX3CR1-GFPhi、Ly6C-单核细胞不同。作为次要假设，我们提出 CD4+ T 细胞可能在慢性感染期间招募或维持 CX3CR1-GFP+ 细胞进入肉芽肿以分化为 AAMF 中发挥作用。因此，我们的具体目标是：（1）使用CX3CR1-GFP报告小鼠观察肝肉芽肿中单核细胞募集和巨噬细胞分化的动态； (2)确定CD4+ TH2细胞在曼氏沙门氏菌卵在肝肉芽肿中募集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，并可能为我们提供调节致病性炎症 Th2 反应的新介入疗法的框架。 公共卫生相关性：2 型 T 辅助细胞条件下激活的巨噬细胞对于伤口愈合、过敏反应和寄生虫感染非常重要。这些细胞如何从血液中的单核细胞募集到组织中尚不清楚。该项目的目标是确定这些巨噬细胞的来源，以便设计有助于调节 2 型反应期间炎症过程的干预策略。