title: Estradiol is a critical mediator of macrophage-nerve cross talk in peritoneal endometriosis.
abstract: Endometriosis occurs in approximately 10% of women and is associated with persistent pelvic pain. It is defined by the presence of endometrial tissue (lesions) outside the uterus, most commonly on the peritoneum. Peripheral neuroinflammation, a process characterized by the infiltration of nerve fibers and macrophages into lesions, plays a pivotal role in endometriosis-associated pain. Our objective was to determine the role of estradiol (E2) in regulating the interaction between macrophages and nerves in peritoneal endometriosis. By using human tissues and a mouse model of endometriosis, we demonstrate that macrophages in lesions recovered from women and mice are immunopositive for estrogen receptor β, with up to 20% being estrogen receptor α positive. In mice, treatment with E2 increased the number of macrophages in lesions as well as concentrations of mRNAs encoded by Csf1, Nt3, and the tyrosine kinase neurotrophin receptor, TrkB. By using in vitro models, we determined that the treatment of rat dorsal root ganglia neurons with E2 increased mRNA concentrations of the chemokine C-C motif ligand 2 that stimulated migration of colony-stimulating factor 1-differentiated macrophages. Conversely, incubation of colony-stimulating factor 1 macrophages with E2 increased concentrations of brain-derived neurotrophic factor and neurotrophin 3, which stimulated neurite outgrowth from ganglia explants. In summary, we demonstrate a key role for E2 in stimulating macrophage-nerve interactions, providing novel evidence that endometriosis is an estrogen-dependent neuroinflammatory disorder.
authors.affiliation: Medical Research Council Centre for Reproductive Health, The University of Edinburgh, Queen's Medical Research Institute, Edinburgh, United Kingdom. Electronic address: egreaves@ed.ac.uk.
authors.forename: Erin
authors.initials: E
authors.lastname: Greaves
authors.affiliation: Endometriosis Centre Charité, Department of Gynecology, Charité, Campus Benjamin Franklin, Berlin, Germany; Department of Biology, Chemistry, and Pharmacy, Free University of Berlin, Berlin, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Temp
authors.affiliation: Medical Research Council Centre for Reproductive Health, The University of Edinburgh, Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors.forename: Arantza
authors.initials: A
authors.lastname: Esnal-Zufiurre
authors.affiliation: Endometriosis Centre Charité, Department of Gynecology, Charité, Campus Benjamin Franklin, Berlin, Germany.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Mechsner
authors.affiliation: Medical Research Council Centre for Reproductive Health, The University of Edinburgh, Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Horne
authors.affiliation: Medical Research Council Centre for Reproductive Health, The University of Edinburgh, Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors.forename: Philippa T K
authors.initials: PT
authors.lastname: Saunders
mesh_terms: D000328:Adult; D000818:Animals; D002450:Cell Communication / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004715:Endometriosis / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology; D047629:Estrogen Receptor beta / Q000378:metabolism*; D005260:Female; D005727:Ganglia, Spinal / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008875:Middle Aged; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010532:Peritoneal Diseases / Q000378:metabolism*; D051381:Rats
chemical_list: D047629:Estrogen Receptor beta; D004958:Estradiol; D016173:Macrophage Colony-Stimulating Factor