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

• DOI: 10.1126/scitranslmed.adk8230
• Publication Date: 2024-11-06T18:58:18Z
• Authors: Victor Fattori; Tiago H. Zaninelli; Fernanda S. Rasqu...; Olivia K. Heintz; Ashish Jain; Liang Sun; Maya L. Seshan; Daniëlle Peterse; Anne E. Lindholm; Raymond M. Anchan; Waldiceu A. Verri; Michael S. Rogers
• Keywords: Nociceptor

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