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，其特征在于异常胶原沉积和瘢痕扩张超过伤口的初始边界1。瘢痕疙瘩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1。虽然瘢痕疙瘩的病理生理学尚不清楚，但来自非洲裔美国人或亚洲背景的个体存在明显的遗传倾向，瘢痕疙瘩患病率分别为7.1%和5.2%，而高加索人为0.5%。除了明显的不必要的美学，瘢痕疙瘩也可以产生瘙痒（痒）和疼痛的感觉3。一项对107例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损害的最强指标，这表明需要治疗来缓解这些感觉。 瘙痒、瘙痒和疼痛源于外周的化学介质激活神经元，其结果是改变我们的行为，以“刮除”刺激或避免有害刺激。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，但细胞和分子原因尚不清楚。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。一个广为人知的领域是神经免疫相互作用;先天性和适应性免疫细胞，如巨噬细胞5和T细胞6，已被证明可以释放促痛觉和痛觉介质，这些介质可以直接作用于神经元，直接激发感觉或导致其敏化7。另一种释放促痛觉介质的非神经元细胞是成纤维细胞8，9。成纤维细胞在体内普遍存在，并通过细胞外基质蛋白（ECM）的重塑定义我们的器官结构，以及提供稳态作用，如免疫稳态和病理功能，包括组织炎症和纤维化10。然而，尽管这些细胞在慢性疼痛性疾病如关节炎中的作用已有记录，但研究成纤维细胞和神经元之间的直接相互作用的研究很少11。皮肤伤口/疤痕环境为这项研究提供了理想的背景。 监督团队（共同监督模式）在这个项目中投入了大量资金，并且完全适合研究瘢痕疙瘩的疼痛。Franziska Denk自2009年以来一直从事疼痛研究，在研究外周神经元和免疫/基质细胞之间的相互作用方面有着良好的记录12，13。Tanya Shaw已经研究伤口修复和瘢痕形成15年了，并且在过去的7年里一直在瘢痕疙瘩方面建立势头。迄今为止，她的重点一直是细胞外基质的病理特征14和疾病的细胞起源15。现在，随着瘙痒和疼痛对患者的重要性，以及促痛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.