Investigating the role of the pattern recognition receptor Nod2 in delayed wound healing in the elderly

大约每20名老年人中就有1人出现无法愈合的皮肤伤口，造成严重的疼痛、痛苦甚至死亡。这些未愈合的伤口也有被有害细菌（病原体）感染的危险。人体通过被称为模式识别受体（PRRs）的特殊受体来识别细菌。它们会对病原体作出反应，并引发免疫反应，杀死病原体。然而，皮肤上覆盖着什么？友好的细菌?正如肠道所显示的那样，这可能有利于伤口愈合。理想情况下，对细菌的免疫反应应该受到严格控制，这样免疫细胞就可以消灭病原体，同时忽略有益的细菌。如果免疫反应没有得到适当的调节，可能会产生严重的后果，包括对友好细菌的不适当的负面反应。维持这种平衡的一种方法是通过下调PRR功能以应对特定细菌，这是由PRR、Nod2和其他基因控制的事件。重要的是，Nod2功能的改变与肠道和皮肤的慢性炎症有关。我们还发现Nod2和其他PRRs在老年人中减少。这表明老年人的皮肤对细菌的免疫反应发生了改变。我们观察到缺乏Nod2的小鼠不能有效地愈合皮肤伤口，在这方面与老年人相似。我们认为Nod2对正常伤口愈合至关重要，其在老年人中的功能降低可能通过改变对细菌的免疫反应来延迟伤口愈合。目前，对慢性延迟愈合的有效治疗方法很少，大多数都侧重于解决症状而不是预防，例如用蛆去除死亡组织。由于人口老龄化，我们迫切需要了解老年人皮肤愈合延迟的原因，这将使我们能够开发更好的治疗方法。该项目的成功完成将揭示Nod2及其与细菌的相互作用在延迟皮肤伤口愈合中的作用。加深对这一关键领域的了解，将有助于开发出更好的慢性皮肤伤口治疗方法。

Approximately, one in twenty elderly people develop skin wounds that do not heal resulting in significant pain, distress and even death. These non-healing wounds are also at risk of becoming infected by harmful bacteria (pathogens). The body recognizes bacteria via specialized receptors called pattern recognition receptors (PRRs). These will respond to pathogens and trigger an immune response to kill the pathogen. However, the skin is covered in ?friendly bacteria? that may, as has been shown in the gut, be beneficial for wound healing. Ideally immune responses to bacteria should be tightly controlled so that the immune cells destroy the pathogens whilst ignoring the friendly bacteria. If the immune responses are not properly regulated there can be serious consequences including an inappropriate negative reaction to friendly bacteria. One way to maintain this balance is by down-regulating PRR function in response to specific bacteria, an event controlled by the PRR, Nod2 and others. Importantly, altered Nod2 function has been linked to chronic inflammation in both the gut and skin. We also have shown that Nod2 and other PRRs are reduced in elderly humans. This suggests that in the skin of older people the immune responses to bacteria are altered. We have observed that mice lacking Nod2 are unable to effectively heal skin wounds and in this respect resemble elderly humans. We believe that Nod2 is critical for normal wound healing and that its reduced function in the elderly delays wound healing, perhaps via altered immune responses to bacteria. At present there are few effective treatments for chronic delayed healing with most focusing on addressing the symptoms rather than prevention e.g. maggots used to remove dead tissue. As we are an aging population, there is an urgent need to understand why skin healing is delayed in the elderly, which will then allow us to develop better treatments. Successful completion of this project will reveal the role of Nod2, and interaction with bacteria, in delayed skin wound healing. Improved understanding of this crucial area will lead to the development of better treatments for chronic skin wounds.