CO-REGULATION OF MACROPHAGE INFLAMMATORY PHENOTYPE BY IRF5 AND RELA

炎症是对感染和损伤的一种正常的、自我限制的生理反应，但如果过度或持续，可导致广泛的组织损伤和残疾。慢性炎症反应的病理后果包括各种具有巨大社会影响的疾病，从自身免疫性疾病，如类风湿关节炎到多种形式的癌症。巨噬细胞是免疫系统的细胞，在体内巡逻，有能力识别感染和损伤过程中释放的许多不同信号。它们在慢性炎性疾病的发病机制中起着至关重要的作用。根据它们接收到的信号类型，巨噬细胞可以获得“侵袭性”炎症表型，并摧毁入侵的威胁和有缺陷的细胞。它们分泌炎症分子，并为具有炎症传播特征的其他类型免疫细胞的扩张创造环境。其他信号会产生更多的“和平”巨噬细胞，促进受损区域的生长和修复。例如，类风湿关节炎的滑膜病变以侵袭性巨噬细胞的存在为特征。最近，我的实验室有了一个潜在的治疗上的重要发现，并确定了一个分子开关，称为“IRF5”，它控制巨噬细胞的侵袭性表型：它在侵袭性巨噬细胞中高度表达，并诱导特征基因表达和炎症分子分泌谱。它对于建立与许多自身免疫性和炎症性疾病相关的炎症环境至关重要，并促进记忆免疫细胞的发育，从而产生更有害的炎症介质。我们还探索了IRF5调节功能的模式，并证明它们涉及与另一种称为NF-kB RelA的分子开关的功能和物理相互作用，这对于侵袭性和和平型巨噬细胞的正常免疫功能都很重要。该项目将验证这样一个假设，即干扰IRF5，特别是其与RelA的相互作用，将会覆盖炎症部位影响侵袭性巨噬细胞发育的信号，并促进它们向更平和的表型转化，从而减少炎症。我们的目的是确定：侵袭性巨噬细胞产生的哪些炎症分子受IRF5和RelA调节，这种控制是如何在分子水平上实现的？2. 我们能否阻断IRF5和RelA之间的直接相互作用，这是否会减少上述炎症分子的产生？这项研究的结果有望成为一种基于最近发现的主要分子开关的调节来控制持续炎症细胞因子产生的新方法的原理证明。后续研究将探讨其他方法调节其活性和功能的可能性，使用化学品，可修改药物开发。考虑到巨噬细胞在任何免疫和炎症条件下的重要作用，确定决定巨噬细胞侵袭性或和平功能的主要分子开关可能是新的治疗干预措施的关键。这是一个重要的研究领域，因为它可能导致新的一类治疗广泛的免疫条件。例如，阻断这些开关的功能可以抑制自身免疫性疾病中存在的破坏性炎症，而诱导它们的功能可以增强免疫抑制患者的免疫系统。

Inflammation is a normal and self-limiting physiological response to infection and injury but can lead to extensive tissue damage and disability when elicited in excess or sustained. Pathological consequences of chronic inflammatory responses include a variety of diseases with huge social impact ranging from autoimmune diseases, such as rheumatoid arthritis to many forms of cancer. Macrophages are cells of the immune system which patrol the body and have the ability to recognise a number of different signals released during infection and damage. They are of central importance in the pathogenesis of chronic inflammatory diseases. Depending on the type of signal they receive, macrophages can acquire "aggressive" inflammatory phenotype and will destroy invading threats and defective cells. They secrete inflammatory molecules and set up an environment for expansion of other types of immune cells with inflammation propagating features. Other signals give rise to more "peaceful" macrophages that promote the growth and repair of damaged regions. For example, synovial lesions in rheumatoid arthritis are characterised by the pre-dominant presence of aggressive macrophages. Recently my laboratory has made a potentially therapeutically important discovery and identified a molecular switch, called 'IRF5' that controls the aggressive phenotype of macrophages: it is highly expressed in aggressive macrophages and induces a characteristic gene expression and inflammatory molecule secretion profile. It is crucially important for establishing an inflammatory environment, associated with a number of autoimmune and inflammatory diseases, and promotes development of memory immune cells which produce even more harmful inflammatory mediators. We have also explored modes of IRF5 regulatory function and demonstrated that they involve functional and physical interactions with another molecular switch, called NF-kB RelA, which is important for proper immune function of both aggressive and peaceful macrophages. This project will test the hypothesis that interfering with IRF5, and in particular with its interactions with RelA, will override signals influencing aggressive macrophage development at sites of inflammation and promote their transformation into more peaceful phenotype, thus reducing inflammation. Our aim is to ascertain: 1. which inflammatory molecules produced by aggressive macrophages are regulated by IRF5 and RelA and how is this control achieved on the molecular level? 2. can we block direct interactions between IRF5 and RelA and would this reduce production of the inflammatory molecules identified above?The outcome of this study is expected to be the proof-of-principle demonstration of a new approach to controlling sustained inflammatory cytokine production, based on modulation of the recently identified major molecular switch. The follow up studies will look into the possibilities of other ways of modulating its activity and function, using chemicals, amendable to drug development. Taking account the essential role of macrophages in any immune and inflammatory condition, identification of major molecular switches that determine aggressive or peaceful function of macrophages may hold the key to new therapeutic interventions. It is an important area of research, as it may result in new class of treatment for a wide range of immune conditions. For example, blocking the function of these switches would dampen down damaging inflammation present in autoimmune diseases, while alternatively, inducing their function would boost the immune system in people with immunosuppression.