The ferroimmunomodulatory role of ectopic endometriotic stromal cells in ovarian endometriosis

Kobayashi, Hiroharu; Yamashita, Yoshihisa; Iwase, Akira; Yoshikawa, Yutaka; Yasui, Hiroyuki; Kawai, Yoshichika; Uchida, Koji; Uno, Nozomi; Akatsuka, Shinya; Takahashi, Takashi; Kikkawa, Fumitaka; Toyokuni, Shinya

doi:10.1016/j.fertnstert.2012.04.047

Cited by 35 publications

(36 citation statements)

References 40 publications

(37 reference statements)

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“…Studies addressing the pathological characteristics of endometriosis have revealed a vicious cycle of oxidative stress generated by high levels of ROS that in turn facilitates the implantation of the ectopic endometrium 26 . Our data support a previously postulated pathomechanistic scenario [12][13][14][15][16][17]39 , whereby retrograde menstruation leads to implantation of endometrium in the peritoneal cavity, which in turn generates a sustained pro-inflammatory environment 11 . This is characterised by increased iron and heme overload through ectopic menstruation and attempted clearance through infiltrating myeloid phagocytes.…”

Section: Discussionsupporting

confidence: 90%

“…Consequently, increased amounts of iron and increased heme catabolism may promote oxidative stress, which is considered to play a key role in the pathophysiology of endometriosis 13 . Indeed, oxidative stress resulting in lipid peroxidation products (LPPs) such as 4-hydroxy-2-nonenal (4-HNE) and malondialdehyde (MDA) has been documented in the stroma of ovarian endometriotic tissue and in the PF of endometriosis patients [14][15][16][17] .…”

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confidence: 99%

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Amine oxidase 3 is a novel pro-inflammatory marker of oxidative stress in peritoneal endometriosis lesions

M-L.

Leo

Laux-Biehlmann

et al. 2020

Sci Rep

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Endometriosis is a common gynaecological disease of women in reproductive age, and is thought to arise from retrograde menstruation and implantation of endometrial tissue, mostly into the peritoneal cavity. The condition is characterized by a chronic, unresolved inflammatory process thereby contributing to pain as cardinal symptom in endometriosis. Elevated reactive oxygen species (ROS) and oxidative stress have been postulated as factors in endometriosis pathogenesis. We here set out for a systematic study to identify novel mechanisms and pathways relating to oxidative stress in ectopic peritoneal lesions. Using combined proteomic and transcriptomic approaches, we identified novel targets including upregulated pro-oxidative enzymes, such as amine oxidase 3/vascular adhesion protein 1 (AOC3/VAP1) as well as downregulated protective factors, in particular alkenal reductase PTGR1 and methionine sulfoxide reductase. Consistent with an altered ROS landscape, we observed hemoglobin / iron overload, ROS production and lipid peroxidation in ectopic lesions. ROS-derived 4-hydroxy-2-nonenal induced interleukin IL-8 release from monocytes. Notably, AOC3 inhibitors provoked analgesic effects in inflammatory pain models in vivo, suggesting potential translational applicability.Endometriosis, affecting 5-10% of women in reproductive age, is a gynaecological disease characterized by the presence of ectopic endometrial tissue most often found in the pelvic cavity 1,2 . Retrograde menstruation is a widely accepted pathogenic mechanism for the formation of peritoneal lesions, in which uterine epithelial and stromal cells are disseminated during menstruation and implanted into the peritoneal cavity via the Fallopian tubes 3,4 . Peritoneal lesions are macroscopically classified based on colour, appearing as white, red, brown, or black lesions. This appearance seems to be determined by endometrial gland content and a variable adjacent stromal reaction, likely reflecting a chronicity process rather than different levels of disease activity 5 . Additional contributors to disease such as genetic, epigenetic and environmental factors exist, since a majority (90%) of women undergo retrograde menstruation associated with successful clearance of menstrual debris from the peritoneal cavity 3,6-9 . However, the formation of ectopic endometrial lesions is a signature event that leads to the hallmarks of disease, comprising sustained inflammation, severe and chronic pain, as well as subfertility 10,11 . www.nature.com/scientificreports www.nature.com/scientificreports/ proteomic and transcriptomic arms of the study distinct patient populations were used and further collection details are provided in the SI material.Protein extraction and sample preparation. Tissue material was homogenised and extracted, protein extracts were subjected to in-solution trypsin digestion and data processed as described 51 . Transcriptome analysis. Illumina compatible next-generation sequencing libraries were prepared and sequenced from ribosomal RNA depleted or...

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Section: Discussionsupporting

confidence: 90%

mentioning

confidence: 99%

Amine oxidase 3 is a novel pro-inflammatory marker of oxidative stress in peritoneal endometriosis lesions

M-L.

Leo

Laux-Biehlmann

et al. 2020

Sci Rep

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“…Higher expression of complement components, e.g. C3, C7, CFH and CFD, in endometriomas has been demonstrated (Kobayashi et al 2012, Suryawanshi et al 2014, Ahn et al 2016) and, in our study, C3 showed the most significantly altered levels between eu-and ectopic endometrial stromal cells (Table 3). Moreover, in our study, complement central components (C3, C7, C1QA and C1QB) as well as complement inhibitors (CD55, CFH, C4BPB, SERPING1 and CLU) were upregulated at the same time.…”

Section: Discussionsupporting

confidence: 77%

“…There are only a few studies utilizing pure cell populations for exploring gene expression in endometriotic lesions. The first study applied laser capture microdissection to gather epithelial cells from eu-and ectopic endometrial tissues (Wu et al 2006), while another study analysed cultured immortalized stromal cells from ovarian endometriosis (Kobayashi et al 2012). The studies investigating gene expression alterations in purified and uncultured stromal cells from eu-and ectopic endometrial tissues are still missing, but could be a helpful source of information to understand the disease pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

High-throughput mRNA sequencing of stromal cells from endometriomas and endometrium

Rekker¹,

Saare²,

Eriste³

et al. 2017

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The aetiology of endometriosis is still unclear and to find mechanisms behind the disease development, it is important to study each cell type from endometrium and ectopic lesions independently. The objective of this study was to uncover complete mRNA profiles in uncultured stromal cells from paired samples of endometriomas and eutopic endometrium. High-throughput mRNA sequencing revealed over 1300 dysregulated genes in stromal cells from ectopic lesions, including several novel genes in the context of endometriosis. Functional annotation analysis of differentially expressed genes highlighted pathways related to cell adhesion, extracellular matrix-receptor interaction and complement and coagulation cascade. Most importantly, we found a simultaneous upregulation of complement system components and inhibitors, indicating major imbalances in complement regulation in ectopic stromal cells. We also performed experiments to evaluate the effect of endometriosis patients' peritoneal fluid (PF) on complement system gene expression levels, but no significant impact of PF on, and levels was observed. In conclusion, the use of isolated stromal cells enables to determine gene expression levels without the background interference of other cell types. In the future, a new standard design studying all cell types from endometriotic lesions separately should be applied to reveal novel mechanisms behind endometriosis pathogenesis.

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“…22 LC/MS/MS analysis was performed as previously described. 23 Fluorescence In Situ Hybridization HCMV BAC DNA was labeled with SpectrumOrange using a Nick Translation Kit (Abbott Molecular, Abbott Park, IL, USA) according to the manufacturer's recommendation and FISH analysis for HCMV genome detection was performed as described previously. 24 …”

Section: Liquid Chromatography-tandem Mass Spectrometry (Lc/ms/ms) Anmentioning

confidence: 99%

Lack of presence of the human cytomegalovirus in human glioblastoma

et al. 2014

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Recent reports have indicated human cytomegalovirus (HCMV) to be associated with human glioblastoma carcinogenesis. In established examples of viral carcinogenesis, viral DNA and one or more of its products have been detected in most tumor cells of biopsies in the majority of cases. To test whether HCMV is associated with human glioblastoma based on this criterion, we measured the number of viral DNA molecules per cell in both frozen and paraffin-embedded tumor biopsies from 58 patients using real-time quantitative PCR (QPCR). Immunohistochemical and fluorescence in situ hybridization (FISH) to detect HCMV proteins and genome was performed in 10 cases using formalin-fixed paraffin-embedded glioblastoma tissues. Southern blotting using DNA extracted from four glioblastoma cell lines together with immunoblotting using the four cell lines and five glioblastoma tissue samples were also performed. We further confirmed the immunoblot bands using liquid chromatography-tandem mass spectrometry assay. As a result, HCMV DNA was not detected in the tumor cells from any of the glioblastoma cases by QPCR detecting two different HCMV genes, in clear contrast to samples from patients with HCMV infection. Southern blotting and immunoblotting of cell lines and FISH using paraffin sections were all negative. However, immunoblotting and immunohistochemistry using tissue samples were partly positive, but HCMV proteins were not detected by proteomic analysis, suggesting false positivity of the analyses. As our QPCR analysis could detect 10 copies of HCMV DNA mixed with DNA extracted from 10 4 HCMV-negative cells, we conclude that HCMV is not persistent, at least in the tumor cells, of developed human glioblastoma.

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The ferroimmunomodulatory role of ectopic endometriotic stromal cells in ovarian endometriosis

Cited by 35 publications

References 40 publications

Amine oxidase 3 is a novel pro-inflammatory marker of oxidative stress in peritoneal endometriosis lesions

Amine oxidase 3 is a novel pro-inflammatory marker of oxidative stress in peritoneal endometriosis lesions

High-throughput mRNA sequencing of stromal cells from endometriomas and endometrium

Lack of presence of the human cytomegalovirus in human glioblastoma

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