A Novel Mouse Model of Endometriosis Mimics Human Phenotype and Reveals Insights into the Inflammatory Contribution of Shed Endometrium

Greaves, Erin; Cousins, Fiona L.; Murray, Alison; Esnal-Zufiaurre, Arantza; Fassbender, Amelie; Horne, Andrew W; Saunders, Philippa T. K.

doi:10.1016/j.ajpath.2014.03.011

Cited by 151 publications

(209 citation statements)

References 44 publications

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“…We have previously reported that Ccl-2 and Ccl-5 (regulated on activation normal T-cell expressed and secreted) mRNA concentrations were elevated in mouse endometriosis lesions, 9 and herein we show that mRNA concentrations of the chemokine Ccl-3 were also significantly elevated in mouse endometriosis lesions (P < 0.01) compared with biopsy specimens of naïve uterus and peritoneum ( Figure 4D). Figure 4 Macrophage infiltration of lesions is estradiol (E2) dependent in a mouse model of endometriosis.…”

Section: Macrophage Infiltration Of Endometriosis Lesions Is E2 Depensupporting

confidence: 71%

“…Specifically, by using in vitro model systems, we found that DRG neurons produced chemokines in response to E2 that promoted macrophage recruitment, whereas macrophages stimulated with E2 produced NTs that promoted neuronal outgrowths. By using a mouse model of endometriosis, 9 we demonstrated that macrophage infiltration of endometriosis lesions was E2 dependent and that the concentrations of mRNAs encoding Csf-1, Nt-3, and TrkB were E2 regulated in mouse lesions.…”

Section: Discussionmentioning

confidence: 91%

“…As we have previously reported data from our mouse model of endometriosis showing that the lesion-resident GFP þ macrophages may originate from both the peritoneum and the shed endometrium, 9 we wondered if the heterogeneous expression of ERa might be a reflection of different origins (endometrial macrophages are all ERa À ), However, because there was no significant difference in proportions of ERa þ cells in lesions and peritoneum, this cannot be the case. It, therefore, remains to be determined what regulates the amount of ERa protein in CD68 þ macrophages.…”

Section: Er Expression By Endometriosis-associated Macrophages Suggesmentioning

confidence: 96%

“…9 In brief, donor endometrial tissue was recovered during induced menses 20 and injected into the peritoneal cavity of recipient mice. Lesions and peritoneum were collected from endometriosis mice (n Z 8) 21 days after inoculation of the peritoneum.…”

Section: Mouse Model Of Endometriosismentioning

confidence: 99%

“…Our studies in a mouse model of endometriosis have revealed that macrophages resident in peritoneal lesions can originate from both the peritoneum and the endometrium. 9 Sensory C, sensory Ad, cholinergic, and adrenergic nerve fibers have been identified within lesions, 10,11 with greater nerve fiber density in areas that exhibit high macrophage density. 6 Studies in zebrafish have shown that macrophages will migrate toward damaged peripheral nerves, 12 consistent with a role for neuron-derived factors in immune-nerve cross talk.…”

mentioning

confidence: 99%

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Estradiol Is a Critical Mediator of Macrophage-Nerve Cross Talk in Peritoneal Endometriosis

Greaves

Temp

Esnal-Zufiurre

et al. 2015

The American Journal of Pathology

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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 b, with up to 20% being estrogen receptor a 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 1edifferentiated macrophages. Conversely, incubation of colony-stimulating factor 1 macrophages with E2 increased concentrations of brainderived 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. Endometriosis affects 10% of reproductive age women and is associated with persistent pelvic pain. 1 It is defined by the presence of endometrial-like tissue (lesions) found outside the uterus, most commonly on the peritoneum. The mechanisms underlying endometriosis-associated pain are poorly understood, but it has been postulated that estrogen-dependent neuroinflammation may be involved. 2 Notably, the presence of endometrial tissue fragments on the peritoneum elicits an immune response, including recruitment of macrophages, 3 blood vessels, and nerve fibers into the resultant lesions. 4,5 Within the lesions, CD68 þ macrophages have been detected in close association with nerve fibers. 6 Studies investigating macrophage activation and recruitment have revealed that endometriosis-associated macrophages exhibit a phenotype consistent with the alternative end of the macrophage activation spectrum. 7,8 In a mouse model of endometriosis that included cell transfer of polarized macrophages, Bacci et al 7 reported that mice injected with proinflammatory macrophages [macrophage (interferon g)] developed microscopic lesions, but those injected with alternatively activated macrophages [macrophage (IL-4)] developed larger lesions with a well-developed vasculature. Our studies in a mouse model of endometriosis have revealed that macrophages resident in peritoneal lesions can originate from both the peritoneum and the endometrium. 9

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Section: Macrophage Infiltration Of Endometriosis Lesions Is E2 Depensupporting

confidence: 71%

Section: Discussionmentioning

confidence: 91%

Section: Er Expression By Endometriosis-associated Macrophages Suggesmentioning

confidence: 96%

Section: Mouse Model Of Endometriosismentioning

confidence: 99%

mentioning

confidence: 99%

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Estradiol Is a Critical Mediator of Macrophage-Nerve Cross Talk in Peritoneal Endometriosis

Greaves

Temp

Esnal-Zufiurre

et al. 2015

The American Journal of Pathology

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136

121

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Female Reproductive System

Dixon¹,

Nikitin²,

Mahler³

2021

Pathology of Genetically Engineered and Other Mutant Mice

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KRAS mutations and endometriosis burden of disease

Orr

Albert

Liu

et al. 2023

The Journal of Pathology CR

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The clinical phenotype of somatic mutations in endometriosis is unknown. The objective was to determine whether somatic KRAS mutations were associated with greater disease burden in endometriosis (i.e. more severe subtypes and higher stage). This prospective longitudinal cohort study included 122 subjects undergoing endometriosis surgery at a tertiary referral center between 2013 and 2017, with 5–9 years of follow‐up. Somatic activating KRAS codon 12 mutations were detected in endometriosis lesions using droplet digital PCR. KRAS mutation status for each subject was coded as present (KRAS mutation in at least one endometriosis sample in a subject) or absent. Standardized clinical phenotyping for each subject was carried out via linkage to a prospective registry. Primary outcome was anatomic disease burden, based on distribution of subtypes (deep infiltrating endometriosis, ovarian endometrioma, and superficial peritoneal endometriosis) and surgical staging (Stages I–IV). Secondary outcomes were markers of surgical difficulty, demographics, pain scores, and risk of re‐operation. KRAS mutation presence was higher in subjects with deep infiltrating endometriosis or endometrioma lesions only (57.9%; 11/19) and subjects with mixed subtypes (60.6%; 40/66), compared with those with superficial endometriosis only (35.1%; 13/37) (p = 0.04). KRAS mutation was present in 27.6% (8/29) of Stage I cases, in comparison to 65.0% (13/20) of Stage II, 63.0% (17/27) of Stage III, and 58.1% (25/43) of Stage IV cases (p = 0.02). KRAS mutation was also associated with greater surgical difficulty (ureterolysis) (relative risk [RR] = 1.47, 95% CI: 1.02–2.11) and non‐Caucasian ethnicity (RR = 0.64, 95% CI: 0.47–0.89). Pain severities did not differ based on KRAS mutation status, at either baseline or follow‐up. Re‐operation rates were low overall, occurring in 17.2% with KRAS mutation compared with 10.3% without (RR = 1.66, 95% CI: 0.66–4.21). In conclusion, KRAS mutations were associated with greater anatomic severity of endometriosis, resulting in increased surgical difficulty. Somatic cancer‐driver mutations may inform a future molecular classification of endometriosis.

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A Novel Mouse Model of Endometriosis Mimics Human Phenotype and Reveals Insights into the Inflammatory Contribution of Shed Endometrium

Cited by 151 publications

References 44 publications

Estradiol Is a Critical Mediator of Macrophage-Nerve Cross Talk in Peritoneal Endometriosis

Estradiol Is a Critical Mediator of Macrophage-Nerve Cross Talk in Peritoneal Endometriosis

Female Reproductive System

KRAS mutations and endometriosis burden of disease

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