The dysregulated IL-23/T H 17 axis in endometriosis pathophysiology

Danielle J Sisnett, Katherine B Zutautas, Jessica E. Miller, Harshavardhan Lingegowda, Soo Hyun Ahn, Alison McCallion, Olga Bougie, Bruce A. Lessey, Chandrakant Tayade
In: bioRxiv · 2023 · doi:10.1101/2023.12.07.570652 · W4389497846
preprint OA: green CC0 ⤵ 1 in-corpus citation
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⚙ AI-generated summary by claude@2026-06, 2026-06-10 ⓘ

This study found dysregulated IL-23/T<sub>H</sub>17 axis gene expression and increased IL-23 in endometriosis patients, and IL-23 treatment promoted pathogenic T<sub>H</sub>17 cells and altered immune cell subsets in mouse models.

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Abstract

Abstract 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 (T H 17) cells, driving T H 17 cells towards a pathogenic profile. In a variety of inflammatory and autoimmune disorders, such as psoriasis and rheumatoid arthritis, T H 17 cells secrete proinflammatory cytokines including IL-17, contributing to the disease pathophysiology. Our studies and others have implicated IL-17 and T H 17 cell dysregulation in endometriosis, which is associated with disease severity. Here we address whether IL-23 driven T H 17 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/T H 17 axis in patient ectopic and eutopic endometrial samples and increased IL-23 protein in patient plasma compared to healthy controls. In-vitro studies using primary human T H cells determined that IL-23 cocktail treatment significantly increased the frequency of pathogenic T H 17 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/T H 17 axis on local immune dysfunction and broadly on the pathophysiology of endometriosis.

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endometriosisinfertility

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