Investigating the cellular and molecular mechanisms of pain and pruritus in pathological keloid scars

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Keloids are a type of pathological scar which are characterised by abnormal collagen deposition and scar expansion beyond the initial boundary of a wound 1. Also referred to as a benign fibroproliferative disorder, keloids are known to continue to grow over time and regrow after resection 1. Though the pathophysiology of keloids is unclear, there are apparent genetic predispositions for individuals from African-American or Asian backgrounds, with 7.1% and 5.2% keloid prevalence, respectively, compared to 0.5% for Caucasians 2. Besides the obvious unwanted aesthetics, keloids can also produce pruritus (itch) and pain sensations 3. A study of 107 patients with keloids showed that pain and itch were the strongest indicators of health-related quality of life impairment, indicating that there is a need for treatment to alleviate these sensations 4. Largely, pruritus and pain derive from neuronal activation by chemical mediators in the periphery, whose outcomes are to alter our behaviour to either 'scratch away' an irritation or avoid noxious stimuli. However, due to the long term and recurring nature of keloids, these sensations become chronic problems, but the cellular and molecular causes are unknown. In recent years, there has been a move away from focusing solely on neuronal changes for explanations of pathological pain, towards looking at the role of non-neuronal cells. A well-published area is that of neuro-immune interactions; both innate and adaptive immune cells, such as macrophages 5 and T-cells 6, have been shown to release pro-algesic and pruritic mediators which can act directly on neurons, either provoking sensation directly or leading to their sensitisation 7. Another type of non-neuronal cell shown to release pro-algesic mediators are fibroblasts 8,9. Fibroblasts are found ubiquitously in the body and define our organ structure via the remodelling of extracellular matrix proteins (ECM), as well as offering homeostatic roles such as immune homeostasis and pathological functions including tissue inflammation and fibrosis 10. However, despite the documented role of these cells in chronically painful diseases such as arthritis, studies looking at the direct interaction between fibroblasts and neurons are sparse 11. The skin wound/scar environment provide an ideal context for this research. The supervisory team (co-supervision model) is heavily invested in this project and are perfectly placed to study pain in keloid scars. Franziska Denk has been in pain research since 2009, has a strong track record in studying the interactions between peripheral neurons and immune/stromal cells 12,13. Tanya Shaw has been studying wound repair and scarring for 15 years and has been building momentum in keloids specifically for the past 7 years. Her focus to date has been on the pathological features of the extracellular matrix 14, and the cellular origin of disease 15. Now, with the importance of itch and pain to the patients, and the likelihood that pro-algesic molecules are further exacerbating the fibrotic response of fibroblasts, this project marks an important progression.