Endometriosis is a common incurable inflammatory disorder that is associated with debilitating pelvic pain in women. Macrophages are central to the pathophysiology of endometriosis: they dictate the growth and vascularization of endometriosis lesions and more recently have been shown to promote lesion innervation. The aim of this study was to determine the mechanistic role of macrophages in producing pain associated with endometriosis. Herein, we show that macrophage depletion in a mouse model of endometriosis can reverse abnormal changes in pain behavior. We identified that disease‐modified macrophages exhibit increased expression of IGF‐1 in an in vitro model of endometriosis‐associated macrophages and confirmed expression by lesion‐resident macrophages in mice and women. Concentrations of IGF‐1 were elevated in peritoneal fluid from women with endometriosis and positively correlate with their pain scores. Mechanistically, we demonstrate that macrophage‐derived IGF‐1 promotes sprouting neurogenesis and nerve sensitization in vitro. Finally, we show that the Igf‐1 receptor inhibitor linsitinib reverses the pain behavior observed in mice with endometriosis. Our data support a role for macrophage‐derived IGF‐1 as a key neurotrophic and sensitizing factor in endometriosis, and we propose that therapies that modify macrophage phenotype may be attractive therapeutic options for the treatment of women with endometriosis‐associated pain.—Forster, R., Sarginson, A., Velichkova, A., Hogg, C., Doming, A., Home, A. W., Saunders, P. T. K., Greaves, E. Macrophage‐derived insulin‐like growth factor‐1 is a key neurotrophic and nerve‐sensitizing factor in pain associated with endometriosis. FASEB J. 33, 11210–11222 (2019). http://www.fasebj.org

Our understanding of the etiology and pathophysiology of endometriosis remains limited. Disease modelling in the field is problematic as many versions of induced mouse models of endometriosis exist. We integrated bioluminescent imaging of ‘lesions’ generated using luciferase-expressing donor mice. We compared longitudinal bioluminescence and histology of lesions, sensory behavior of mice with induced endometriosis and the impact of the GnRH antagonist Cetrorelix on lesion regression and sensory behavior. Four models of endometriosis were tested. We found that the nature of the donor uterine material was a key determinant of how chronic the lesions were as well as their cellular composition. The severity of pain-like behavior also varied across models. Whilst Cetrorelix significantly reduced lesion bioluminescence in all models, it had varying impacts on pain-like behavior. Collectively, our results demonstrate key differences in the progression of the ‘disease’ across different mouse models of endometriosis. We propose that validation and testing in multiple models, each of which may be representative of the different subtypes / heterogeneity observed in women should become a standard approach to discovery science in the field of endometriosis.