by Justin Jackson , Medical Xpress Image of a mouse endometriosis lesion stained for nerves (red) and a peptide released by nerves (CGRP, green) that helps endometriosis lesions grow. Credit: Dr. Victor Fattori and Dr. Michael Rogers Boston Children’s Hospital and Harvard Medical School researchers have discovered a neuroimmune communication pathway that may drive endometriosis-associated pain and lesion growth. Endometriosis is a debilitating inflammatory disease affecting up to 15% of women and is characterized by the growth of endometrial-like tissue outside the uterus. Treatments can currently only target symptoms, with over-the-counter pain medicines and hormonal birth control, or in some cases, surgery. Endometriosis occurs when cell tissues normally found within the uterus lining take root in areas outside the uterus. This tissue is hormonally sensitive and can become inflamed, especially during menstrual cycles, and can cause severe cramping, pain, and other symptoms depending on the area affected. Because of the abnormal location, the endometrial-like tissues do not vacate during menstruation as similar cells within the lining do. Instead, they can form scar tissues, cysts, lesions, nodules, and connective tissues that can bind to other organs. In a study, “Nociceptor-to-macrophage communication through CGRP/RAMP1 signaling drives endometriosis-associated pain and lesion growth in mice,” published in Science Translational Medicine, the research teams focused on the gene-related peptide (CGRP) and its receptor peptide RAMP1 revealed the nociceptor-to-macrophage communication pathway. The pain-relieving effect of rimegepant in a mouse model of endometriosis. Just before mice were given endometriosis, their abdominal pain threshold was measured, and then measured every week afterward; a lower threshold indicates more pain. After 4 weeks, the mice were given rimegepant daily at a low and higher dose. The rise in threshold indicates that pain was relieved. Credit: Dr. Victor Fattori and Dr. Michael Rogers Using samples from eight patients with endometriosis and a mouse model of the disease, the researchers found that both human and mouse endometriosis lesions contain CGRP and its coreceptor RAMP1. In mice, the team reduced the activity of nociceptors (nerve cells responsible for sensing pain) by employing genetic techniques and chemical treatments. They bred mice to lack specific nociceptor cells and used compounds like resiniferatoxin to deactivate these nerves chemically. This led to decreased pain behaviors and smaller lesion sizes, suggesting that active nociceptors contribute to disease progression. To understand how lesions affect nerve cells, they exposed mouse nerve cells to substances extracted from the lesions. The nerve cells activated, indicating that the lesions can directly stimulate nerves. This was shown by measuring calcium levels in the nerve cells, a sign of activation. Further investigation revealed that CGRP released by these activated nerves altered macrophages into a pro-endometriosis phenotype. These CGRP-stimulated macrophages exhibited impaired efferocytosis (immune process of clearing dead cells) and promoted increased growth of endometrial cells in a RAMP1-dependent manner. This suggests that CGRP signaling through RAMP1 on macrophages plays a crucial role in lesion growth and pain associated with endometriosis. Treatment with FDA-approved drugs that block the CGRP-RAMP1 signaling pathway, including medications typically used for migraines, reduced pain and lesion size in the mice, suggesting a potential new application for these drugs. By uncovering this nociceptor-to-macrophage communication pathway, the study suggests that targeting CGRP/RAMP1 signaling may offer new avenues for clinical intervention. Further research is needed to explore the applicability of these findings to human patients and assess the long-term efficacy of CGRP/RAMP1-targeting therapies. More information: Victor Fattori et al, Nociceptor-to-macrophage communication through CGRP/RAMP1 signaling drives endometriosis-associated pain and lesion growth in mice, Science Translational Medicine (2024). DOI: 10.1126/scitranslmed.adk8230 Journal information: Science Translational Medicine  © 2024 Science X Network Explore further Long-acting recycling antibody targets endometriosis