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

巨噬细胞在先天免疫和适应性免疫系统中发挥着关键作用。一方面，它们对病原体的摄取、杀伤和降解以及抗原的加工和呈递至关重要。另一方面，它们对炎症过程的终止和组织稳态的恢复至关重要。为了实现所有这些功能，巨噬细胞可以表达大量的激活状态，从经典活化的巨噬细胞（M1巨噬细胞）到交替活化的巨噬细胞（M2巨噬细胞）。虽然关于活化B细胞的转录因子核因子kappa-轻链增强子（NF-kB）在巨噬细胞功能中的作用的大量信息存在，但关于AP-1转录因子在此背景下的作用知之甚少。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的激活。由于Fra蛋白是AP-1中研究最少的成员，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，我们将在体外描述fr -1或fr -2缺失如何影响巨噬细胞对不同刺激的反应，包括巨噬细胞的促炎、轻度刺激或抗炎反应。除了这些典型的极化刺激，Fra蛋白的功能也将在单核增生李斯特菌（L.m）感染中得到解决，以揭示它们对巨噬细胞至关重要的抗微生物活性的影响。计算网络分析将使用RNA测序和ChIP测序对不同的刺激进行，以获得Fra依赖性激活的无偏结果。为了将我们的发现转移到体内，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。将使用两种小鼠疾病模型，李斯特菌病和类风湿性关节炎，使我们能够表征在急性或慢性炎症过程中巨噬细胞中Fra蛋白的重要性。我们研究的长期目标是确定巨噬细胞极化调节是否适合终止炎症过程和恢复组织稳态。

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.