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AP-1 transcription factors roles in the control of macrophage polarization

AP-1 转录因子在控制巨噬细胞极化中的作用

基本信息

批准号：
387043890
负责人：
Professorin Dr. Aline Bozec, Ph.D.
金额：
--
依托单位：
Medizinische Klinik 3 - Rheumatologie und Immunologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2017
资助国家：
德国
起止时间：
2016-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/387043890?language=en
关键词：
AP transcription factors roles control

项目摘要

Macrophages play pivotal roles in the innate and adaptive immune system. On one side, they are essential for the uptake, killing and degradation of pathogens and for the processing and presentation of antigens. On the other side, they are crucial for the termination of inflammatory processes and the restoration of tissue homeostasis. To fulfil all these functions, macrophages can express a large spectrum of activation statuses ranging from classically activated macrophages (M1 macrophages) to the alternatively activated macrophages (M2 macrophages). While substantial information on the role of the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) exist in macrophage functions, few is known about the role of AP-1 transcription factor in this context.Our project aims to determine how the AP-1 transcription factor family regulates macrophage activation. Since Fra proteins are the least AP-1 members studied, we will have a particular interest on the role of Fra-1 and Fra-2 proteins in macrophages. First, we will characterize in vitro how Fra-1 or Fra-2 deletion affects the response of macrophages to different stimuli covering from pro-inflammatory, mild stimulatory or anti-inflammatory responses in macrophages. In addition to these canonical polarisation stimuli, the function of the Fra proteins will also be addressed in infections with Listeria monocytogenes (L.m.) to unravel their impact on the crucial anti-microbial activity of macrophages. A computational network analysis will be performed for the different stimuli using RNA sequencing and ChIP sequencing to get unbiased results of Fra dependent activation. To transfer our finding in vivo, we will study the genetically engineered mouse models for Fra-1 or Fra-2 deleted specifically in the myeloid lineage. Two murine disease models, listeriosis and rheumatoid arthritis will be used, allowing us to characterize the importance of Fra proteins in macrophages during acute or chronic inflammatory processes.The long term aim of our research is to define whether modulation of macrophage polarization is suitable to terminate the inflammatory processes and to restore the tissue homeostasis.

巨噬细胞在先天性和适应性免疫系统中起关键作用。一方面，它们对于病原体的吸收、杀灭和降解以及抗原的加工和呈递是必不可少的。另一方面，它们对于终止炎症过程和恢复组织稳态至关重要。为了实现所有这些功能，巨噬细胞可以表达大范围的活化状态，从经典活化的巨噬细胞（M1巨噬细胞）到替代活化的巨噬细胞（M2巨噬细胞）。虽然大量的信息的作用，转录因子活化B细胞的核因子κ轻链增强子（NF-κ B）存在于巨噬细胞的功能，很少有人知道AP-1转录因子在这方面的作用，我们的项目旨在确定AP-1转录因子家族如何调节巨噬细胞活化。由于Fra蛋白是研究的AP-1成员中最少的，因此我们将对Fra-1和Fra-2蛋白在巨噬细胞中的作用特别感兴趣。首先，我们将在体外表征Fra-1或Fra-2缺失如何影响巨噬细胞对不同刺激的反应，包括巨噬细胞中的促炎、轻度刺激或抗炎反应。除了这些典型的极化刺激之外，Fra蛋白的功能也将在单核细胞增生李斯特菌（Listeria monocytogenes，L.m.）以揭示它们对巨噬细胞关键的抗微生物活性的影响。将使用RNA测序和ChIP测序对不同刺激进行计算网络分析，以获得Fra依赖性激活的无偏结果。为了在体内转移我们的发现，我们将研究在骨髓谱系中特异性缺失Fra-1或Fra-2的基因工程小鼠模型。我们将使用两种小鼠疾病模型，类风湿性关节炎和类风湿性关节炎，使我们能够表征Fra蛋白在巨噬细胞在急性或慢性炎症过程中的重要性，我们研究的长期目标是确定巨噬细胞极化的调节是否适合于终止炎症过程并恢复组织稳态。