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

瘢痕疙瘩是一种病理性瘢痕，其特征是异常胶原沉积和瘢痕扩展超出伤口的初始边界1。也被称为良性纤维增生性疾病，已知瘢痕疙瘩会随着时间的推移继续生长，并在切除后重新生长。虽然瘢痕疙瘩的病理生理机制尚不清楚，但非洲裔美国人和亚裔背景的人有明显的遗传易感性，瘢痕疙瘩患病率分别为7.1%和5.2%，而白种人为0.5% 2。除了明显不美观之外，瘢痕疙瘩还会引起瘙痒和疼痛感。一项对107名瘢痕疙瘩患者的研究表明，疼痛和瘙痒是与健康相关的生活质量受损的最强指标，表明需要治疗来减轻这些感觉。在很大程度上，瘙痒和疼痛源于周围化学介质的神经元激活，其结果是改变我们的行为，要么“刮掉”刺激，要么避开有害的刺激。然而，由于瘢痕疙瘩的长期性和复发性，这些感觉成为慢性问题，但细胞和分子的原因是未知的。近年来，人们已经从仅仅关注神经元的变化来解释病理性疼痛，转向关注非神经元细胞的作用。一个发表得很好的领域是神经免疫相互作用；先天免疫细胞和适应性免疫细胞，如巨噬细胞和t细胞，都释放出能直接作用于神经元的促痛觉和瘙痒介质，要么直接激发感觉，要么导致其致敏。另一种显示释放促痛觉介质的非神经元细胞是成纤维细胞8,9。成纤维细胞在体内无处不在，通过重塑细胞外基质蛋白（ECM）来定义我们的器官结构，并提供稳态作用，如免疫稳态和病理功能，包括组织炎症和纤维化。然而，尽管这些细胞在关节炎等慢性疼痛疾病中发挥了文献记载的作用，但针对成纤维细胞和神经元之间直接相互作用的研究却很少。皮肤伤口/疤痕环境为这项研究提供了一个理想的环境。监督团队（联合监督模式）在这个项目上投入了大量资金，非常适合研究瘢痕疙瘩疤痕的疼痛。Franziska Denk自2009年以来一直从事疼痛研究，在研究周围神经元和免疫/基质细胞之间的相互作用方面有着良好的记录12,13。坦尼娅·肖研究伤口修复和疤痕已有15年，在过去的7年里，她一直在研究瘢痕疙瘩。迄今为止，她的研究重点是细胞外基质的病理特征和疾病的细胞起源。现在，随着瘙痒和疼痛对患者的重要性，以及促痛觉分子进一步加剧成纤维细胞纤维化反应的可能性，该项目标志着一个重要的进展。

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.