An investigation of the IL-23/Th17 axis and transcriptomic profiles of T helper subsets in endometriosis

Danielle J Sisnett, Katherine B Zutautas, Holmes JP, Jaelis P. Holmes, Jessica Pudwell, Kira King, King K, Olga Bougie, Tayade C, Chandrakant Tayade
In: bioRxiv · 2026 · doi:10.64898/2026.06.11.731688 · W7164534376
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⚙ AI-generated summary by claude@2026-07, 2026-07-09 ⓘ

This study characterized T helper cell subsets in endometriosis patients by profiling immune mediators and transcriptomes, revealing significant immune remodeling and an aberrant Th17 cell phenotype, particularly in severe disease stages.

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The paper investigated the IL-23/Th17 axis and bulk transcriptomic profiles of T helper subsets in endometriosis, using systemic (plasma), local (peritoneal fluid), and tissue samples (matched eutopic and ectopic) from endometriosis patients across stages and healthy controls, with cytokine/chemokine profiling, flow cytometry, and bulk RNA sequencing of Th1, Th1/17, and Th17 subsets. Severe-stage disease showed altered immune mediators including elevated IL-6 in plasma, FLT-3L and G-CSF in eutopic tissue, and IL-1RA and IL-23 (p40) in peritoneal fluid, alongside flow cytometry evidence of increased pathogenic Th17 cells in peritoneal fluid and higher circulating Th17 cells in mild versus severe stages. RNA sequencing identified extensive reprogramming of Th subsets in endometriosis, with the largest differential gene expression changes in Th17 cells (2,220 DEGs). A key limitation acknowledged by the authors is the focus on bulk RNA sequencing profiles rather than single-cell functional validation across subsets and stages. This paper is centrally about endometriosis — it characterizes IL-23/Th17-driven remodeling and transcriptomic changes in Th17 cells across endometriosis stages.

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Abstract

Abstract Endometriosis (EMS) is a chronic inflammatory disease characterized by ectopic endometrial-like tissue growth and immune dysregulation. Aberrant T cell responses are implicated in EMS pathogenesis, however, functional reprogramming of T helper (Th) subsets across disease stages remain unclear. We profiled systemic and local immune mediators (cytokines/chemokines) and performed bulk RNA sequencing to comprehensively characterize Th1, Th1/17, and Th17 cell subsets from EMS patients and healthy controls. Across patient plasma, peritoneal fluid (PF), and matched eutopic and ectopic tissues, we observed systemic and local cytokine/chemokine alterations, including elevated IL-6 (plasma), FLT-3L and G-CSF (eutopic), and IL-1RA and IL-23 (p40; PF) in severe-stage EMS. Flow cytometry depicted elevated pathogenic Th17 cells in patient PF compared to matched non-pathogenic Th17 and Treg cell subsets. Additionally, circulating Th17 cells were increased in patients with mild (stages I-II) relative to severe (stages III-IV) EMS. RNA sequencing revealed extensive Th subset reprogramming in EMS, most predominately in Th17 cells (2,220 DEGs). Collectively, we reveal significant immune remodeling in EMS and highlight a distinct, aberrant Th17 cell phenotype. Results support repurposing of IL-23- and IL-17-targeted therapeutics, already effectively implemented in other chronic inflammatory diseases, to broaden therapeutic options for EMS and associated comorbidities.
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Abstract Endometriosis (EMS) is a chronic inflammatory disease characterized by ectopic endometrial-like tissue growth and immune dysregulation. Aberrant T cell responses are implicated in EMS pathogenesis, however, functional reprogramming of T helper (Th) subsets across disease stages remain unclear. We profiled systemic and local immune mediators (cytokines/chemokines) and performed bulk RNA sequencing to comprehensively characterize Th1, Th1/17, and Th17 cell subsets from EMS patients and healthy controls. Across patient plasma, peritoneal fluid (PF), and matched eutopic and ectopic tissues, we observed systemic and local cytokine/chemokine alterations, including elevated IL-6 (plasma), FLT-3L and G-CSF (eutopic), and IL-1RA and IL-23 (p40; PF) in severe-stage EMS. Flow cytometry depicted elevated pathogenic Th17 cells in patient PF compared to matched non-pathogenic Th17 and Treg cell subsets. Additionally, circulating Th17 cells were increased in patients with mild (stages I-II) relative to severe (stages III-IV) EMS. RNA sequencing revealed extensive Th subset reprogramming in EMS, most predominately in Th17 cells (2,220 DEGs). Collectively, we reveal significant immune remodeling in EMS and highlight a distinct, aberrant Th17 cell phenotype. Results support repurposing of IL-23- and IL-17-targeted therapeutics, already effectively implemented in other chronic inflammatory diseases, to broaden therapeutic options for EMS and associated comorbidities. Competing Interest Statement The authors have declared no competing interest.

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