Nociceptor-to-macrophage communication through CGRP/RAMP1 signaling drives endometriosis-associated pain and lesion growth in mice

IF 15.8 1区 医学 Q1 CELL BIOLOGY
Victor Fattori, Tiago H. Zaninelli, Fernanda S. Rasquel-Oliveira, Olivia K. Heintz, Ashish Jain, Liang Sun, Maya L. Seshan, Daniëlle Peterse, Anne E. Lindholm, Raymond M. Anchan, Waldiceu A. Verri Jr., Michael S. Rogers
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Abstract

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.
通过 CGRP/RAMP1 信号传导,痛觉感受器与巨噬细胞之间的交流驱动了小鼠子宫内膜异位症相关疼痛和病灶生长
子宫内膜异位症是一种使人衰弱和痛苦的妇科炎症,影响多达 15%的女性和变性男性。目前的治疗方法对相当一部分患者无效,因此需要更多具有长期疗效的疗法。痛觉感受器会释放降钙素基因相关肽(CGRP)等神经肽,众所周知,降钙素基因相关肽可通过神经免疫通讯影响免疫力。鉴于子宫内膜异位症和偏头痛之间的并发症以及免疫细胞和炎症在子宫内膜异位症中不可或缺的作用,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。利用八名子宫内膜异位症患者的样本和非手术治疗的小鼠模型,我们发现小鼠和人类子宫内膜异位症病灶中都含有 CGRP 及其核心受体--受体活性修饰蛋白 1(RAMP1)。在小鼠中,痛觉感受器消融可减轻疼痛、单核细胞募集和病变大小,这表明痛觉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。从机理上讲,CGRP 改变了巨噬细胞的表型,使其变成了有利于子宫内膜异位症的表型。CGRP刺激的巨噬细胞表现出排泄功能受损,并以依赖RAMP1的方式支持子宫内膜细胞生长。用美国食品和药物管理局批准的阻断 CGRP-RAMP1 信号的药物治疗有病变的小鼠,可减少机械性痛觉减退、自发性疼痛和病变大小。总之,我们的数据证明了在子宫内膜异位症小鼠模型中阻断非激素和非阿片类 CGRP/RAMP1 信号的有效性和潜在细胞机制,这表明针对这一轴心可能会给子宫内膜异位症患者带来临床益处。
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来源期刊
Science Translational Medicine
Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL
CiteScore
26.70
自引率
1.20%
发文量
309
审稿时长
1.7 months
期刊介绍: Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.
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