Neuroinflammation in endometriosis: macrophages behaving badly?

子宫内膜异位症是一种炎症性疾病，定义为子宫内膜（子宫内膜）在子宫外的存在，最常见的是在盆腔壁的内衬上（“子宫内膜异位症病变”）。这被认为是通过一种被称为“逆行排卵”的现象发生的，在月经期间脱落的子宫内膜通过输卵管回流到盆腔。子宫内膜异位症影响着英国大约150万妇女，大多数患有子宫内膜异位症的妇女也有使人衰弱的盆腔疼痛。治疗患有子宫内膜异位症的妇女和相关的生产力损失所产生的费用估计为每年117亿英镑。子宫内膜异位症可以手术治疗或使用抑制激素的药物治疗，但手术后症状通常会复发，并且可用的药物治疗具有不良的副作用。女性需要新的治疗方法来减轻痛苦。为什么子宫内膜异位症会引起疼痛还不清楚，但我相信这是由于新神经生长到病变中以及炎症分子（神经炎症）的刺激。值得注意的是，子宫内膜异位症也可以发现与疼痛敏感性的普遍增加有关。免疫细胞，如巨噬细胞在炎症过程中至关重要。每个组织都有自己的“类型”的巨噬细胞，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以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，反映了人类的状况。病变的形成方式与人类相似，小鼠也表现出与糖尿病相关的疼痛。使用这个模型，我已经表明，巨噬细胞从盆腔迁移到病变。值得注意的是，我还首次表明，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促进神经炎症，炎症相关疼痛以及随后对疼痛敏感性的增加。我的具体目标有四个方面：首先，我将使用一个实验室小鼠月经和子宫内膜异位症模型来研究月经时脱落的子宫内膜中存在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，我将通过使用在实验室中生长的痛觉神经来确定在先前的目标中已经确定的巨噬细胞产生的因子如何与神经相互作用。最后，我将确定巨噬细胞是否在炎症相关疼痛和对疼痛的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。我已经开发了创新的新模型，并产生了令人兴奋的和信息丰富的新的初步数据，我相信我可以实现指定的目标。我相信，在这次奖学金期间产生的信息将导致高质量的高影响力的出版物，对子宫内膜异位症如何引起疼痛的新认识，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.