Role of Mef2D in inflammation

免疫系统对于防止感染和调节组织修复是必不可少的。尽管免疫系统具有这些重要功能，但如果调节不当，可能会产生有害影响。感染后，免疫系统中的细胞检测到病原体，然后引发炎症反应。这一过程导致进一步的免疫细胞的招募和激活，旨在杀死病原体。一旦病原体被清除，免疫系统就会失活，这一过程被称为消解。虽然炎症是应对感染的一个必要过程，但这个过程的一个副作用是对身体健康细胞的不必要的附带损害。为了最大限度地减少这种影响，炎症是一个受到严格控制的过程，并受到一系列正反馈和负反馈机制的影响，以防止不受控制的炎症，并在病原体被杀死后促进其消退。炎症期间免疫细胞的协调是通过产生一系列促炎和抗炎细胞因子实现的，这些细胞因子是控制免疫细胞功能的小蛋白。由于它们在调节免疫系统中的重要性，这些细胞因子的产生受到严格的调控，这种调控的失败会造成严重的后果。例如，在感染过程中未能限制炎症可能导致不受控制的促炎细胞因子的产生，即使感染得到控制，这种细胞因子也会持续存在。这些“细胞因子风暴”会导致败血症休克，治疗起来非常困难，但仍会导致高死亡率。无法促进炎症的消退或免疫耐受性的崩溃会导致慢性炎症，这种疾病是一系列疾病的病理基础，包括自身免疫性疾病、糖尿病和心血管疾病。因此，调节细胞因子的产生或功能以使免疫系统失活的药物有可能治疗一系列疾病。了解调节细胞因子产生的细胞内机制及其对免疫系统的影响是选择可用于药物开发的靶点的重要第一步。我们感兴趣的是抗炎细胞因子IL-10的产生是如何被控制的。IL-10是抑制炎症、促进消退的关键细胞因子。这一发现说明了这一点，即要么使IL-10基因失活，要么阻止IL-10功能的突变，由于对肠道菌群的免疫反应失控，导致小鼠和人类结肠炎的发生。此外，在免疫模型上，IL-10功能的丧失已被证明在很大程度上使小鼠对病理敏感。在我们之前的工作中，我们已经研究了IL-10基因的转录是如何被调控的，并开始解开控制其表达的细胞内途径。最近我们发现，在天然免疫的重要细胞类型巨噬细胞中，IL-10的产生被Mef2D抑制，Mef2D是一种先前未确定在巨噬细胞功能中发挥作用的蛋白质。Mef2D是一种能与DNA结合并调节特定基因转录的转录因子，在IL-10基因中存在一个潜在的Mef2D位点。在这项拟议的工作中，我们将确定Mef2D调节巨噬细胞中IL-10的分子机制以及控制Mef2D功能的信号通路。我们还将确定Mef2D是否在免疫系统中产生IL-10的其他类型的细胞中发挥类似的作用。最后，我们将确定体内阻断Mef2D功能对IL-10依赖的免疫疾病模型有什么影响。总之，这些实验将有助于描绘一条控制IL-10产生的新途径。这反过来将提出新的方法，使IL-10的产生成为旨在限制炎症的药物的靶点。

The immune system is essential in order to protect from infection and to mediate tissue repair. Despite these important functions the immune system, when not correctly regulated, can have harmful effects. Following infection, pathogens are detected by cells in the immune system, which then trigger an inflammatory reaction. This process results in the recruitment and activation of further immune cells and is designed to kill the pathogen. Once the pathogen is cleared then the immune system is deactivated, a process referred to as resolution. While inflammation is a necessary process to deal with infection, a side effect of this process is unwanted collateral damage to healthy cells in the body. To minimize this effect, inflammation is a tightly controlled process and subject to a range of both positive and negative feedback mechanisms to both prevent uncontrolled inflammation and promote its resolution once pathogens are killed. Co-ordination of immune cells during inflammation is achieved via the production of a range of pro- and anti-inflammatory cytokines, small proteins that control the function of immune cells. Due to their importance in regulating the immune system, the production of these cytokines is tightly regulated and failure of this regulation has serious consequences. For example, failure to limit inflammation during infection can lead to a uncontrolled production of pro-inflammatory cytokines that persists even if the infection is controlled. These 'cytokine storms' can lead to septic shock and are very difficult to treat and still result in a high rate of mortality. An inability to promote the resolution of inflammation or a breakdown in immune tolerance results in chronic inflammation, a condition that underlies pathology in a range of diseases including autoimmune conditions, diabetes and cardiovascular disease.Drugs that modulate the production or function of cytokines to inactivate the immune system therefore have potential for the treatment of a range of conditions. Understanding the intracellular mechanisms that regulate cytokine production and how this impacts on the immune system is an important first step in selecting targets that can be used for drug development. We are interested in how the production of an anti-inflammatory cytokine, IL-10, is controlled. IL-10 is a key cytokine in limiting inflammation and promoting resolution. This is illustrated by the finding that mutations that either inactivate the IL-10 gene or block IL-10 function result in the development of colitis in both mice and humans due to a deregulated immune response to the gut flora. In addition loss of IL-10 function has been shown to sensitize mice to pathology in a large range on immune models. In our previous work, we have looked at how transcription of the IL-10 gene is regulated and started to unravel the intracellular pathways that control its expression. Recently we have found that in macrophages, an important cell type in innate immunity, IL-10 production is inhibited by Mef2D, a protein that was not previously established to play a role in macrophage function. Mef2D is a transcription factor that can bind to DNA and regulate the transcription of specific genes and a potential site for Mef2D exists in the IL-10 gene. In the proposed work, we will determine the molecular mechanism by which Mef2D regulates IL-10 in macrophages and the signaling pathways that control Mef2D function. We will also determine if Mef2D plays a similar role in other cell types in the immune system that produce IL-10. Finally we will determine what the effect blocking Mef2D function in vivo has on IL-10 dependent models of immune disease. Together these experiments will help delineate a new pathway that controls the production of IL-10. This in turn will suggest novel ways in which IL-10 production could be targeted by drugs designed to limit inflammation.