Estradiol is a critical mediator of macrophage-nerve cross talk in peritoneal endometriosis
Open accessAbstract
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.
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Increased density of sensory nerves in or around DE lesions results from neurotrophic factors secreted by endometriotic lesions or platelets.
“Moreover, the increased density of sensory nerves in or around DE lesions also results from neurotrophic factors secreted by endometriotic lesions84,87–90 or platelets84.”
From Neuropeptides Substance P and Calcitonin Gene Related Peptide Accelerate the Development and Fibrogenesis of Endometriosis (2019) · cites this paper as [90]
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“Peritoneal fluid macrophages from women with endometriosis upregulate the expression of ERβ and in a mouse model of endometriosis E2 treatment increases the macrophages present in lesions as well as the expression of macrophage migration factor [51, 52].”
BackgroundEndometriosis and nuclear receptors
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“In common with other immune cells found in the endometrium (macrophages, mast cells [55,56]), uNK cells express ERbeta [18].”
BackgroundSelf-citation
- Authors
- Greaves, E., Temp, J., Esnal-Zufiurre, A., Mechsner, S., Horne, A. W., & Saunders, P. T. K.
- Affiliations
- MRC Centre for Reproductive Health (GB)
- Stiftung Charité (DE)
- Corresponding author
- Greaves, Erin
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2015-08
- Volume
- 185
- Issue
- 8
- Pages
- 2286-2297
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC4530129
- OpenAlex
- W2121381144
- Cited by
- 201
- References
- 43
- Citations by year
- 2026: 14 · 2025: 21 · 2024: 46 · 2023: 24 · 2022: 15 · 2021: 18 · 2020: 19 · 2019: 13 · 2018: 14 · 2017: 11 · 2016: 3 · 2015: 3
- FWCI
- 11.79
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (submittedVersion, other-oa)
- Warwick Research Archive Portal (University of Warwick) (submittedVersion)
- Funders
- Wellbeing of Women (R42533)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Endometriosis Research and Treatment
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Keywords
- peritoneal endometriosis, estradiol, neuroinflammation, estrogen receptor beta, estrogen receptor alpha, CSF-1, colony-stimulating factor 1, neurotrophin-3, brain-derived neurotrophic factor, TrkB, MCP-1, macrophage migration, dorsal root ganglion neurons, neurite outgrowth, endometriosis-associated pain, estrogen dependence
- MeSH terms
- Adult, Animals, Cell Communication, Cell Differentiation, Cell Movement, Disease Models, Animal, Endometriosis, Estradiol, Female, Ganglia, Spinal, Humans, Macrophages, Middle Aged, Neurons, Peritoneal Diseases, Macrophage Colony-Stimulating Factor, Estrogen Receptor beta, Mice, Rats
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