Neuroinflammation in endometriosis: macrophages behaving badly?

子宫内膜异位症是一种炎症性疾病，由子宫外子宫内膜（子宫内膜）的存在所定义，最常见于盆腔壁的内膜（“子宫内膜异位症病变”）。这被认为是通过一种被称为“逆行月经”的现象发生的，在月经期间脱落的子宫内膜通过输卵管向后回流到盆腔。在英国，子宫内膜异位症影响了大约150万女性，而且大多数患有子宫内膜异位症的女性还伴有骨盆疼痛。据估计，每年用于治疗子宫内膜异位症和相关生产力损失的费用为117亿英镑。子宫内膜异位症可以通过手术或使用抑制激素的药物治疗，但手术后症状通常会复发，现有的药物治疗有不良的副作用。女性需要新的治疗方法来减轻她们的痛苦。子宫内膜异位症引起疼痛的原因尚不清楚，但我认为这是由于新神经在病变处生长，并受到炎症分子（神经炎症）的刺激。值得注意的是，子宫内膜异位症也与疼痛敏感性增加有关。免疫细胞，如巨噬细胞在炎症过程中起关键作用。每个组织都有自己的“类型”巨噬细胞，它们已被确定为子宫内膜异位症疾病进展中的重要细胞。我们不知道巨噬细胞如何影响子宫内膜异位症的神经生长或导致疼痛。然而，我最近表明，在实验室中操纵巨噬细胞来模拟子宫内膜异位症病变中发现的巨噬细胞会增加神经生长和炎症。我开发了一种新的子宫内膜异位症实验小鼠模型，它反映了人类的情况。病变形成的方式与人类相似，小鼠也表现出子宫内膜异位症相关的疼痛。使用这个模型，我已经证明巨噬细胞从盆腔迁移到病变。值得注意的是，我也首次证明了在月经时脱落的子宫内膜中存在的巨噬细胞也在病变中存活。这个模型将使我能够确定巨噬细胞如何导致神经炎症、子宫内膜异位症相关的疼痛以及随后对疼痛的敏感性增加。我的具体目标有四个方面；首先，我将利用“月经”和子宫内膜异位症的实验室小鼠模型，研究月经时存在于脱落子宫内膜中的巨噬细胞如何影响子宫内膜异位症病变的形成。其次，我将确定巨噬细胞如何影响子宫内膜异位症病变中的神经生长和神经炎症。第三，我将通过实验室培养的痛觉神经来确定巨噬细胞产生的因子是如何与神经相互作用的。最后，我将确定巨噬细胞是否在子宫内膜异位症相关疼痛和疼痛敏感性增加中发挥作用，并发现抑制巨噬细胞产生的因子是否可以减轻这种疼痛。我开发了创新的新模型，并提供了令人兴奋和信息丰富的新颖初步数据，我有信心能够实现指定的目标。我相信在这次交流中产生的信息将导致高质量的高影响力出版物，对子宫内膜异位症如何引起疼痛的新理解，并将为治疗子宫内膜异位症相关疼痛提供新的方法。

Endometriosis is an inflammatory condition, defined by the presence of womb lining (endometrium) outside the womb, most commonly on the lining of the wall of the pelvic cavity ('endometriosis lesions'). This is thought to occur via a phenomenon known as 'retrograde menstruation', where the endometrium that is shed during menstruation is refluxed backwards through the Fallopian tubes into the pelvic cavity. Endometriosis affects approx.1.5 million women in the UK and a large majority of women with endometriosis also have debilitating pelvic pain. Costs incurred by treating women with endometriosis and associated loss of productivity are estimated at £11.7 billion per year. Endometriosis is treated surgically or with drugs that suppress hormones, but symptoms usually recur after surgery and the available medical treatments have undesirable side effects. Women want new treatments to ease their suffering. Why endometriosis causes pain is poorly understood but I believe that it is due to the growth of new nerves into the lesions and their stimulation by molecules involved in inflammation (neuroinflammation). Notably, endometriosis can also be found associated with a general increased sensitivity to pain. Immune cells, such as macrophages are critical in the inflammatory process. Each tissue has its own 'type' of macrophage and they have been identified as important cells in the disease progression of endometriosis. We do not know how macrophages affect nerve growth in endometriosis or contribute to pain in the condition. However, I have recently shown that macrophages manipulated in the laboratory to mimic macrophages found in endometriosis lesions increase nerve growth and inflammation. I have developed a novel experimental mouse model of endometriosis that mirrors the human condition. The lesions form in a similar way to the human, and the mice also exhibit endometriosis-associated pain. Using this model I have shown that macrophages from the pelvic cavity migrate into lesions. Notably, for the first time I have also shown that macrophages present in the shed endometrium at the time of menstruation also survive in the lesions. This model will allow me to determine how macrophages contribute to neuroinflammation, endometriosis-associated pain and subsequent increases in sensitivity to pain. My specific aims are fourfold; firstly I will investigate how macrophages, that are present in the shed endometrium at the time menstruation, influence the formation of endometriosis lesions using a laboratory mouse model of 'menstruation' and endometriosis. Secondly, I will determine how macrophages influence nerve growth and neuroinflammation in endometriosis lesions. Thirdly, I will determine how factors produced by macrophages that have been identified in the previous objective, interact with nerves by using pain-sensing nerves grown in the laboratory. Finally, I will determine if macrophages play a role in endometriosis-associated pain and general increased sensitivity to pain, and to discover whether inhibition of factors produced by macrophages can reduce this pain.I have developed innovative new models and produced exciting and informative novel preliminary data and I am confident that I can deliver the specified aims. I believe that information generated during this fellowship will lead to quality high impact publications, new understanding of how endometriosis causes pain and will inform new ways to treat endometriosis-associated pain.