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

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.

Non-healing chronic wounds in the elderly are a major cause of patient morbidity and mortality and a substantial burden on the NHS. A key problem with non-healing ulcers is persistent infection due to pathogenic bacterial colonisation. In addition, the skin has a substantial, but poorly characterised, commensal microflora that may also contribute to local inflammation. In the gut, chronic inflammation can be caused by dysregulated immune responses to both commensal microflora and pathogens. We know that the interaction of commensals with mucosa, via pattern recognition receptors (PRRs), is critical for gut barrier function and wound repair. Here we propose a similar role for specific PRRs in skin homeostasis and hypothesise that disrupted PRR function in the elderly leads to delayed skin repair due either to impaired response to commensals or exaggerated response to pathogens. To support this theory, our preliminary microarray studies of delayed skin wound healing in the elderly reveal downregulation of multiple PRRs, including nucleotide oligomerisation domain 2 (Nod2). Interestingly, Nod2, in addition to mediating recognition of bacteria, has been implicated in down-modulating the pro-inflammatory cascade initiated by the major PRR, TLR2. Moreover, human Nod2 mutations are associated with chronic inflammatory conditions of both gut and skin. Crucially, our novel pilot data reveal a pronounced delayed healing phenotype in Nod2 null mice mirroring that seen in elderly humans. Thus, we hypothesise that altered Nod2 function is an important contributing factor to delayed wound repair in the elderly. This project will elucidate the role of Nod2 in delayed skin wound healing using a combination of in vitro and in vivo anlaysis in mouse models together with validation in human samples, and experimental manipulation in a murine model of delayed human healing. Our goal is to understand the cell-type specific contribution of Nod2 to delayed healing in the elderly and explore the potential for therapeutic modulation.