O-078 Deletion of interlukin-17A protects against ovarian aging via activating wnt10b/β-catenin signaling

Abstract

Abstract Study question Is there any compelling evidence to suggest that the deletion of IL17A could potentially ameliorate ovarian aging? Summary answer IL17A is elevated in the follicular fluid of aged women. Knocking out Il17a in mice improves ovarian aging phenotypes by activating Wnt10b/β-catenin signaling. What is known already Inflammation, a hallmark of aging, negatively impacts female fertility. Interleukin 17 (IL-17) cytokines, including IL-17A, IL-17B, IL-17C, IL-17D, IL-17E, and IL-17F, are signature cytokines of T helper 17 cells. IL-17A, the first-discovered and well-explored among them, has been predominantly characterized as a kind of proinflammatory cytokine and a promoter in the pathogenesis of chronic autoimmune diseases such as psoriasis and ankylosing spondylitis. Significant accumulation of CD4-CD8-double-negative T cells in aged mouse ovaries, identified as a crucial source of IL-17, was reported via single-cell RNA sequencing. However, much remains unknown about the IL17 and ovarian aging relationship. Study design, size, duration Follicular fluid was collected from 51 women (age≥35 years) and 37 controls (age <35 years) at the Southern Medical University Southern Hospital's Reproductive Center to measure IL17A levels from March 2022 to August 2023. Additionally, we generated Il-17a knockout (Il17-a KO) mice (42 KO mice and 49 controls) to elucidate the role of Il-17a in ovarian aging in vivo. Further, RNA-seq was employed to explore the mechanism involved in the Il17a-associated ovarian aging. Participants/materials, setting, methods Clinical data were compared from two infertile patient cohorts. IL17A levels in follicular fluid were quantified using ELISA. Pearson correlation analysis explored the relationship between IL17A levels and age, ovarian reserve, and clinical outcomes. We also assessed aging-related phenotypes in Il17a-KO and WT mice at 3, 8, 12, and 15 months of age. Fertility assessment, ovarian reserve, histological analysis, mason staining, western blot analysis, qRT-PCR, IVF, spindle formation, and RNA-seq were used in this study. Main results and the role of chance Elevated IL17A levels in follicular fluid from aged patients were observed and may be used as a sensitive biomarker for advanced age (P < 0.001). Deletion of Il17a not only enhanced fertility and ovarian reserve in mice but also ameliorated inflammation, the senescent associated secretory phenotype (SASP), senescence and fibrosis. RNA-seq analysis identified 705 differentially expressed genes, primarily enriched in the Wnt10b signaling pathway. Validation experiments suggested that IL-17A deficiency may improve ovarian aging by upregulating wnt10b expression, promoting β-catenin nuclear translocation, and activating downstream molecules (c-Myc, Cyclin D1, c-jun). Limitations, reasons for caution This study found a correlation between IL17A and aging. However, how knocking out IL17A promotes the increase of Wnt10b and other potential functions of Il17a in ovarian aging remain to be further explored. Wider implications of the findings This study shows new insights into the mechanisms of IL17A in ovarian aging and provides potential biomarkers and therapeutic targets for the treatment of ovarian aging. In the future, a larger sample of studies are needed to investigate the relationship between IL17A and aged women. Trial registration number not applicable