Genetic dissection of the mechanisms coordinating immunity and metabolism

免疫和代谢功能的整合是正常发育和健康寿命的基础。当免疫系统对压力做出反应并对抗病原体时，代谢系统在能量储存和消耗之间协调平衡。由于免疫激活在能量上是昂贵的，在维持其他重要过程的同时，需要精确的协调来建立有效的防御。代谢和免疫功能是由共享或重叠的进化保守信号通路控制的，其破坏是几种人类疾病的基础，包括糖尿病、代谢综合征、慢性炎症性疾病和癌症。因此，破译新陈代谢和免疫之间的联系因素是一个重要的研究方向。应激诱导的激活转录因子3 （Atf3）已经成为NF-κ b介导的免疫反应的一个强有力的负调节因子，并且在肥胖、克罗恩病或癌症患者中观察到Atf3表达的变化。我们使用果蝇模型的工作表明，Atf3的表达在果蝇发育过程中受到严格调控，在任何方向上操纵其水平都会产生有害的后果。我们确定了Atf3作为免疫和代谢稳态的保障。我们发现，atf3的丢失导致脂质过载和失控的炎症，导致能量失衡和过早死亡。我们进一步证明，Atf3的表达会随着上皮完整性的破坏而上升，其异位活性会干扰上皮形态发生，这源于细胞骨架动力学、细胞粘附和细胞内运输的干扰。Atf3活性失调与免疫和代谢失衡、细胞结构改变和人类疾病的关联要求我们更好地了解Atf3在正常和病理环境下的功能。基于我们已发表的和初步的数据，利用果蝇模型，本提案旨在(1)识别和表征由Atf3控制的脂肪组织特异性遗传程序，这是免疫和代谢稳态的关键；(2)定义驱动免疫细胞与脂肪组织相互作用的机制；(3)确定受损的微管细胞骨架和细胞运输如何促进由Atf3功能障碍引起的免疫代谢表型。(4)确定Atf3在免疫细胞中的作用。我们的工作将为转录因子控制免疫和代谢稳态、协调免疫细胞功能和协调器官间通讯的机制提供新的见解。我们希望找到可以在调节组织生理和炎症代谢疾病的背景下利用的效应物。我们相信我们提出的项目将对基础研究和生物医学研究具有普遍的重要性。

Integration of immune and metabolic functions is fundamental for normal development and healthy lifespan. While the immune system responds to stress and fights off pathogens, the metabolic system orchestrates a balance between energy storage and expenditure. As immune activation is energetically costly, precise coordination is needed to mount an effective defense while sustaining other vital processes. The metabolic and immune functions are controlled by shared or overlapping evolutionarily conserved signaling pathways, disruption of which underlies several human diseases including diabetes, metabolic syndrome, chronic inflammatory disorders and cancer. Deciphering the factors that link metabolism and immunity is, therefore, of major interest. The stress inducible Activating transcription factor 3 (Atf3) has emerged as a potent negative regulator of NF-κB-mediated immune responses and changes to Atf3 expression have been observed in patients suffering from obesity, Crohn’s disease or cancer. Our work using the Drosophila model showed that Atf3 expression is tightly regulated during fly development and manipulating its levels in either direction has detrimental consequences. We established Atf3 as a safeguard of immune and metabolic homeostasis. We showed that loss of atf3 resulted in lipid overload and runaway inflammation, causing energy imbalance and premature death. We further demonstrated that Atf3 expression rises in response to a breakdown of epithelial integrity and its ectopic activity interferes with epithelial morphogenesis, stemming from disturbed cytoskeleton dynamics, cell adhesion and intracellular trafficking . The association of deregulated Atf3 activity with immune and metabolic imbalance, altered cytoarchitecture and human diseases calls for a better understanding of Atf3 function in both normal and pathological settings. Building on our published and preliminary data, utilizing Drosophila model, this proposal aims (1) to identify and characterize the adipose tissue-specific genetic program controlled by Atf3 that is key to immune and metabolic homeostasis, (2) to define mechanisms that drive immune cell interactions with the adipose tissue, (3) to determine how impairing microtubule cytoskeleton and cellular trafficking contribute to the immune-metabolic phenotypes caused by Atf3 malfunction, and (4) to determine the role of Atf3 in immune cells. Our work will provide novel insights into mechanisms by which transcription factors control immune and metabolic homeostasis, orchestrate immune cell functions and coordinate inter-organ communication. We hope to identify effectors that can be exploited in the context of regulating tissue physiology and inflammatory-metabolic diseases. We believe our proposed project will be of general importance for basic as well as biomedical research.