The Role of the IL-23/Th17/IL-17 Axis in the Pathophysiology of Endometriosis

Endometriosis (EM) is a chronic inflammatory disease whereby endometrial-like tissue grows ectopically, commonly presenting as dyspareunia, dysmenorrhea, and infertility. Due to invasive diagnosis, disease heterogeneity, and reproductive disorder stigmatization, patients often experience misdiagnosis and significant diagnostic delays. No reliable, non-invasive, non-hormonal therapeutic options exist, significantly impacting quality of life and ability to conceive. While EM etiology and pathogenesis remain unclear, immune dysfunction is recognized to enable lesion establishment and progression. Notably, the IL-23/Th17/IL-17 axis is significantly altered in EM and associated with disease severity. This is notable as in other chronic inflammatory diseases, IL-23 drives pathogenic Th17 responses, producing IL-17 to exacerbate disease. Th17 cells are also highly plastic and can transdifferentiate into T regulatory (Tregs) and Th1 cells. As a balanced Th17:Treg ratio is essential for immune homeostasis, it is necessary to define their contributions in EM, particularly under the influence of IL-23. We aimed to address knowledge gaps by comprehensively examining this axis in EM pathophysiology using in-vitro and in-vivo techniques to assess systemic and localized influences of IL-23. Results depict significant dysregulation of the IL-23/Th17/IL-17 axis at the mRNA and protein level within human patient samples and our established mouse model of EM. Indeed, EM patients have significantly increased circulating IL-23 and IL-23 promotes the development of pathogenic Th17 cells, which can exacerbate hallmark features of EM, including angiogenesis, proliferation, and vascularization. Using matched patient samples, we depict significant alterations to key immune mediators in EM, including some alterations that are associated with disease stage. Moreover, we depict that in-vivo IL-23 treatment significantly altered numbers of myeloid and T cell subsets in mouse peritoneal fluid and increased giant cells within lesions. Finally, transcriptomic analysis of circulating Th1, Th1/17, and Th17 cells revealed these subsets to have unique transcriptional profiles in EM patients compared to controls, with Th17 cells being significantly reprogrammed in EM compared to Th1 cells. Ultimately, we identify IL-23 and IL-17 as potential novel therapeutic targets for EM patients. As therapeutics already exist successfully targeting these cytokines in other disease contexts, this may allow for drug repurposing and greatly reduce the immense burden of EM.

Department dc:contributor.department

Biomedical and Molecular Sciences

Year dc:date.issued

2026

Author dc:creator

• Sisnett, Danielle

Advisor dc:contributor.supervisor

• Tayade, Chandrakant

• Th17 cells
• IL-17
• IL-23
• Endometriosis
• Immune Dysfunction
• Chronic Inflammation
• T regulatory cells

Statement dc:rights

• Attribution 4.0 International

Licence dc:rights.uri

• https://creativecommons.org/licenses/by/4.0/

Language dc:language.iso

eng

Handle dc:identifier.uri

https://hdl.handle.net/1974/36181

OAI identifier oai:identifier

oai:queensu.scholaris.ca:1974/36181