Treatment of inflammation via activation of the mRNA-destabilising protein tristetraprolin

炎症是对感染或身体损害的一种健康反应，有助于消除有害微生物。然而，在炎症反应过程中释放的许多因子无法区分自身和微生物，因此有可能对炎症组织造成附带损害。出于这个原因，炎症通常受到非常严格的控制。健康的炎症反应有一个快速的起效和一个有序的消退阶段，在这个阶段，被激活的免疫细胞离开炎症组织或返回到它们的静止状态。这使得受影响组织的正常功能可以在最小损害的情况下恢复。发炎可以被认为是油门踏板，解决方案是刹车：安全驾驶需要明智地使用两者。没有得到充分控制的破坏性炎症是类风湿性关节炎、慢性阻塞性肺疾病、炎症性肠病等许多慢性病的典型特征。不受控制的炎症也会导致心血管疾病、阿尔茨海默病等神经退行性疾病以及多种形式的癌症。几十年来，研究人员对这些疾病的主要关注点一直是识别炎症的诱因，并试图阻止它们的影响。这一方法只取得了一定程度的成功，在发达国家，慢性炎症性疾病造成的总体经济、社会和个人负担继续增加。对炎症诱因的关注有忽视同样重要的解决过程的风险。来自人类疾病的基因研究和动物实验的证据清楚地表明，炎症性疾病可能是由于作为解决方案的“刹车”机制的缺陷而引起或恶化的。越来越多的研究人员现在正试图了解炎症消退所涉及的生物过程。人们认为加强分解机制可能是治疗炎症性疾病的有效方法。我们对一种名为Tristetraprolin(TTP)的蛋白质的研究发展了增强分解的概念。不能产生TTP的小鼠会发生严重的自发性炎症性疾病，因此我们知道TTP是炎症的重要刹车。我们还了解到，TTP的功能由一个分子开关控制，该开关将TTP在活动状态和非活动状态之间进行转换。我们可以在类风湿关节炎患者的慢性炎症关节中检测到大量的TTP蛋白，但它似乎处于非活动状态。我们怀疑，TTP的持续失活阻止了炎症的消退，就像故障的刹车一样。我们相信，通过恢复TTP的功能，有效修复受损的刹车，将有可能减少炎症。为此，我们计划使用两种不同的药物，我们预测这两种药物将把TTP从非激活状态转换为激活状态。这些药物中的一种已经用于治疗多发性硬化症，而另一种正在作为癌症的潜在治疗方法进行研究。如果这项工作取得成功，可能会导致新的临床试验，并最终产生一种全新的炎症性疾病治疗方法，一种基于促进消退而不是阻止炎症触发因素的治疗方法。

Inflammation is a healthy response to infection or physical damage, which helps to eliminate harmful microbes. However, many of the factors released during an inflammatory response cannot discriminate between self and microbe, and therefore risk causing collateral damage to the inflamed tissue. For this reason, inflammation is usually very tightly regulated. A healthy inflammatory response has a rapid onset and an orderly resolution phase, in which activated immune cells exit the inflamed tissue or return to their resting state. This allows normal function of the affected tissue to be restored with minimal damage. An inflammatory trigger can be thought of as an accelerator pedal, and resolution as the brake: safe driving requires judicious use of both.Inadequately controlled, damaging inflammation is the defining characteristic of chronic diseases like rheumatoid arthritis, chronic obstructive pulmonary disease, inflammatory bowel disease and many others. Uncontrolled inflammation also strongly contributes to cardiovascular disease, neurodegenerative conditions like Alzheimer's disease, and many forms of cancer. For decades the main focus of researchers on these diseases has been to identify triggers of inflammation and try to block their effects. This approach has met with only moderate success, and the overall economic, societal and personal burdens of chronic inflammatory disease continue to grow in the developed world. The focus on triggers of inflammation risks overlooking the equally important process of resolution. Evidence both from genetic studies of human disease and from animal experiments clearly shows that inflammatory disease can be caused or made worse by defects in the "braking" mechanisms that underlie resolution. More and more researchers are now trying to understand the biological processes involved in the resolution of inflammation. It is thought that reinforcement of resolution mechanisms may be an effective way to treat inflammatory diseases.Our research on a protein called tristetraprolin (TTP) develops the concept of reinforcing resolution. Mice that cannot produce TTP develop severe, spontaneous inflammatory disease, therefore we know that TTP is an important brake to inflammation. We have also learned that the function of TTP is controlled by a molecular switch that converts it between active and inactive states. We can detect a lot of TTP protein in chronically inflamed joints of patients with rheumatoid arthritis, but it seems to be in the inactive state. We suspect that the persistent inactivation of TTP prevents resolution of inflammation, much like a faulty brake. We believe it will be possible to reduce inflammation by restoring the function of TTP, effectively repairing the damaged brake. To do this, we plan to use two different drugs that we predict will switch TTP from inactive to active state. One of these drugs is already used to treat multiple sclerosis, whilst the other is being investigated as a potential treatment for cancer. If this work is successful it may lead to new clinical trials, and ultimately to an entirely new type of treatment for inflammatory diseases, one that is based on promoting resolution rather than blocking inflammatory triggers.