Endometriosis is a debilitating and painful gynecological inflammatory disease affecting up to 15% of women and transgender men. Current treatments are ineffective for a substantial proportion of patients, underscoring the need for additional therapies with long-term benefits. Nociceptors release neuropeptides, such as calcitonin gene–related peptide (CGRP), which are known to shape immunity through neuroimmune communication. Given the comorbidity between endometriosis and migraine and the integral role of immune cells and inflammation in endometriosis, we investigated the role of CGRP-mediated neuroimmune communication in endometriosis. Using samples from eight patients with endometriosis and a nonsurgical mouse model of the disease, we found that mouse and human endometriosis lesions contain both CGRP and its coreceptor, receptor activity modifying protein 1 (RAMP1). In mice, nociceptor ablation reduced pain, monocyte recruitment, and lesion size, suggesting that nociceptor activation and neuropeptide release contribute to endometriosis lesion growth and pain. Mechanistically, CGRP changed the phenotype of macrophages to a pro-endometriosis phenotype. CGRP-stimulated macrophages demonstrated impaired efferocytosis and supported increased endometrial cell growth in a RAMP1-dependent manner. Treatment of lesion-bearing mice with US Food and Drug Administration–approved drugs that block CGRP-RAMP1 signaling reduced mechanical hyperalgesia, spontaneous pain, and lesion size. Together, our data demonstrated the effectiveness and underlying cellular mechanisms of nonhormonal and nonopioid CGRP/RAMP1 blockade in a mouse model of endometriosis, suggesting that targeting this axis may lead to clinical benefit for patients with endometriosis.

中文翻译：

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通过 CGRP/RAMP1 信号传导的伤害感受器与巨噬细胞通讯驱动小鼠子宫内膜异位症相关的疼痛和病变生长


子宫内膜异位症是一种使人衰弱和痛苦的妇科炎症性疾病，影响多达 15% 的女性和跨性别男性。目前的治疗对很大一部分患者无效，这凸显了需要具有长期益处的额外疗法。伤害感受器释放神经肽，例如降钙素基因相关肽 （CGRP），已知这些肽可通过神经免疫通讯塑造免疫力。鉴于子宫内膜异位症和偏头痛之间的共病以及免疫细胞和炎症在子宫内膜异位症中的整体作用，我们研究了 CGRP 介导的神经免疫通讯在子宫内膜异位症中的作用。使用来自 8 名子宫内膜异位症患者的样本和该疾病的非手术小鼠模型，我们发现小鼠和人子宫内膜异位症病变同时包含 CGRP 及其辅助受体受体活性修饰蛋白 1 （RAMP1）。在小鼠中，伤害感受器消融减轻了疼痛、单核细胞募集和病变大小，表明伤害感受器激活和神经肽释放有助于子宫内膜异位症病变的生长和疼痛。从机制上讲，CGRP 将巨噬细胞的表型改变为促子宫内膜异位症表型。CGRP 刺激的巨噬细胞表现出胞吐作用受损，并以 RAMP1 依赖性方式支持子宫内膜细胞生长增加。用美国食品和药物管理局批准的阻断 CGRP-RAMP1 信号传导的药物治疗带病灶的小鼠可减少机械痛觉过敏、自发性疼痛和病变大小。总之，我们的数据证明了非激素和非阿片类药物 CGRP/RAMP1 阻断在子宫内膜异位症小鼠模型中的有效性和潜在的细胞机制，表明靶向该轴可能为子宫内膜异位症患者带来临床益处。