T helper 17 axis and endometrial macrophage disruption in menstrual effluent provides potential insights into the pathogenesis of endometriosis

Miller, Jessica E.; Lingegowda, Harshavardhan; Sisnett, Danielle J.; Metz, Christine N.; Gregersen, Peter K.; Koti, Madhuri; Tayade, Chandrakant

doi:10.1016/j.xfss.2022.04.007

Cited by 5 publications

(5 citation statements)

References 38 publications

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“…This scenario suggests a skewed T H 17/T REG axis towards a tolerant (T REG dominant) microenvironment as lesions initially establish, followed by a proinflammatory (T H 17 dominant) microenvironment allowing for lesion survival, as downstream T H 17 cytokines, such as IL-17, are well-known to promote lesion angiogenesis, proliferation, and inflammation 10,27,28 . Results from our lab support this theory, finding T H 17 cells to be significantly decreased in patient menstrual effluent as compared to controls 29 . Based on the theory of retrograde menstruation, this data provides insights into early events in endometriosis lesion establishment.…”

Section: Introductionsupporting

confidence: 70%

“…Additionally, IL-17 is produced by lesions and following excision surgery, a significant reduction of systemic IL-17 levels was reported 10 , highlighting the potential link between IL-17 and endometriosis. Furthermore, T H 17 cells are dysregulated in endometriosis 24,29,33 and are also associated with disease severity 13 . Thus, while this downstream cytokine in the T H 17 axis has been examined in endometriosis, there is a gap in knowledge as to what is driving T H 17/IL-17 axis dysregulation in endometriosis.…”

Section: Discussionmentioning

confidence: 99%

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The dysregulated IL-23/T_H17 axis in endometriosis pathophysiology

Sisnett,

Zutautas,

Miller

et al. 2023

Preprint

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Endometriosis is a chronic inflammatory disease where endometrial-like tissue grows ectopically, resulting in pelvic pain and infertility. Interleukin (IL)-23 is established as a key contributor in the development and differentiation of a subset of T cells known as T-helper 17 (TH17) cells, driving TH17 cells towards a pathogenic profile. In a variety of inflammatory and autoimmune disorders, such as psoriasis and rheumatoid arthritis, TH17 cells secrete proinflammatory cytokines including IL-17, contributing to the disease pathophysiology. Our studies and others have implicated IL-17 and TH17 cell dysregulation in endometriosis, which is associated with disease severity. Here we address whether IL-23 driven TH17 cells contribute to the cardinal features of lesion proliferation, vascularization, and inflammation in endometriosis using patient samples, representative cell lines, and our established mouse model of endometriosis. Our results indicate significantly dysregulated expression of key genes in the IL-23/TH17 axis in patient ectopic and eutopic endometrial samples and increased IL-23 protein in patient plasma compared to healthy controls.In-vitrostudies using primary human THcells determined that IL-23 cocktail treatment significantly increased the frequency of pathogenic TH17 cells. Similarly, treatment with recombinant human (rh)IL-23 on cell lines (12Z, EECC, HUVEC, and hESC) representative of the endometriotic lesion microenvironment led to a significant increase in cytokines and growth factors known to play a role in lesion establishment and maintenance. In a syngeneic mouse model of endometriosis, treatment with recombinant mouse (rm)IL-23 led to significant alterations in numbers of myeloid and T cell subsets in peritoneal fluid and significantly increased numbers of giant cells within the lesion. Endometriotic lesions from rmIL-23 mice did not reveal significant alterations in proliferation and vascularization, although trends of increased proliferation and vascularization were observed. Collectively, these findings provide insights into the impact of the IL-23/TH17 axis on local immune dysfunction and broadly on the pathophysiology of endometriosis.

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Section: Introductionsupporting

confidence: 70%

Section: Discussionmentioning

confidence: 99%

The dysregulated IL-23/T_H17 axis in endometriosis pathophysiology

Sisnett,

Zutautas,

Miller

et al. 2023

Preprint

Self Cite

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“…Loss of CXCR4, the receptor for CXCL12, in response to OCPs is also interesting, as this has been reported to reduce proliferation and lesion number in endometriosis [50]. Blocking CXCL12/CXCR4 actions also decreases invasion and migration of the endometriotic 12Z cell line [51]. Finally, IL-23a and its association with the IL-17 axis promotes endometriosis and is involved in the pathogenesis of this disease [52].…”

Section: Discussionmentioning

confidence: 98%

Inflammatory Changes after Medical Suppression of Suspected Endometriosis for Implantation Failure: Preliminary Results

Lessey,

Dong,

Deaton

et al. 2024

IJMS

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Unexplained euploid embryo transfer failure (UEETF) is a frustrating and unanswered conundrum accounting for 30 to 50% of failures in in vitro fertilization using preimplantation genetic testing for aneuploidy (PGT-A). Endometriosis is thought by many to account for most of such losses and menstrual suppression or surgery prior to the next transfer has been reported to be beneficial. In this study, we performed endometrial biopsy in a subset of women with UEETF, testing for the oncogene BCL6 and the histone deacetylase SIRT1. We compared 205 PGT-A cycles outcomes and provide those results following treatment with GnRH agonist versus controls (no treatment). Based on these and previous promising results, we next performed a pilot randomized controlled trial comparing the orally active GnRH antagonist, elagolix, to oral contraceptive pill (OCP) suppression for 2 months before the next euploid embryo transfer, and monitored inflammation and miRNA expression in blood, before and after treatment. These studies support a role for endometriosis in UEETF and suggest that medical suppression of suspected disease with GnRH antagonist prior to the next transfer could improve success rates and address underlying inflammatory and epigenetic changes associated with UEETF.

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“…To study immunological differences in menstruation between healthy subjects and those with endometriosis, Miller et al [ 58 ] recruited healthy volunteers without endometriosis and those with endometriosis and collected menstrual effluent (ME) from these subjects during their menstrual periods. ME was centrifuged, with ME cells separated from supernatant “serum”, and multiplex cytokine analysis was conducted.…”

Section: Interplay Between Endometrium and Immune System Revealed Thr...mentioning

confidence: 99%

“…They further identified 47 DEGs in the MEs between groups, and in particular determined that genes related to the T H 17 axis such as IL10 , IL23A , and IL6 were downregulated in subjects with endometriosis. Likewise, macrophage-associated genes such as CD74 , CD83 , CXCL16 and CCL3 were downregulated in the ME of subjects with endometriosis [ 58 ].…”

Section: Interplay Between Endometrium and Immune System Revealed Thr...mentioning

confidence: 99%

Uterine Transcriptome: Understanding Physiology and Disease Processes

Kirschen

Hessami

AlAshqar

et al. 2023

Biology

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In recent years, transcriptomics has enabled us to gain a deeper understanding of fundamental reproductive physiology, including the menstrual cycle, through a more precise molecular analysis. The endometrial mRNA transcript levels fluctuate during the normal menstrual cycle, indicating changes in the relative recruitment and abundance of inflammatory cells, as well as changes in the receptivity and remodeling of the endometrium. In addition to providing a more comprehensive understanding of the molecular underpinnings of pathological gynecological conditions such as endometriosis, leiomyomas, and adenomyosis through RNA sequencing, this has allowed researchers to create transcriptome profiles during both normal menstrual cycles and pathological gynecological conditions. Such insights could potentially lead to more targeted and personalized therapies for benign gynecological conditions. Here, we provide an overview of recent advances in transcriptome analysis of normal and pathological endometrium.

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T helper 17 axis and endometrial macrophage disruption in menstrual effluent provides potential insights into the pathogenesis of endometriosis

Cited by 5 publications

References 38 publications

The dysregulated IL-23/T_H17 axis in endometriosis pathophysiology

The dysregulated IL-23/T_H17 axis in endometriosis pathophysiology

Inflammatory Changes after Medical Suppression of Suspected Endometriosis for Implantation Failure: Preliminary Results

Uterine Transcriptome: Understanding Physiology and Disease Processes

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T helper 17 axis and endometrial macrophage disruption in menstrual effluent provides potential insights into the pathogenesis of endometriosis

Cited by 5 publications

References 38 publications

The dysregulated IL-23/TH17 axis in endometriosis pathophysiology

The dysregulated IL-23/TH17 axis in endometriosis pathophysiology

Inflammatory Changes after Medical Suppression of Suspected Endometriosis for Implantation Failure: Preliminary Results

Uterine Transcriptome: Understanding Physiology and Disease Processes

Contact Info

Product

Resources

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The dysregulated IL-23/T_H17 axis in endometriosis pathophysiology

The dysregulated IL-23/T_H17 axis in endometriosis pathophysiology