| Abstract |
Polycystic ovary syndrome (PCOS) represents a prevalent endocrine disorder that constitutes a significant threat to female reproductive health. Immune dysregulation and chronic low-grade inflammation are increasingly recognized as pivotal contributors to ovarian dysfunction in this condition. In the present study, we enrolled PCOS patients clinically and established a dehydroepiandrosterone (DHEA)-induced PCOS mouse model. Our findings revealed elevated levels of pro-inflammatory M1 macrophages, diminished anti-inflammatory M2 macrophages, and aberrant distribution of associated inflammatory cytokines in both PCOS patients and animal models, implicating the macrophage phenotypic plasticity in the pathogenesis of PCOS. Interleukin-4 (IL-4), a potent immunomodulatory cytokine, effectively ameliorated ovarian histopathological alterations and restored ovulatory function in the DHEA-induced PCOS mice through the promotion of M2 macrophage polarization. Specifically, IL-4 administration attenuated serum concentrations of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α), concomitantly enhancing interleukin-10 (IL-10) and interferon-γ (IFN-γ) expression, whilst suppressing M1 macrophage infiltration. Furthermore, IL-4 treatment mitigated ovarian cellular apoptosis, upregulated ADAM metallopeptidase with thrombospondin type 1 motif 1 (ADAMTS1) expression, and reinstated ovulatory capacity. Mechanistically, IL-4 facilitated M2 macrophage polarization via the modulation of the nuclear factor-κB (NF-κB) signaling pathway; these polarized M2 macrophages subsequently attenuated apoptosis in co-cultured KGN granulosa cells and enhanced ADAMTS1 expression. This investigation preliminarily elucidates novel insights into the inflammatory and immune microenvironment underlying PCOS pathophysiology, demonstrating that IL-4 could ameliorate ovarian apoptosis and promote ovulatory function through NF-κB/IκB-mediated M2 macrophage polarization, thereby alleviating PCOS-associated manifestations and furnishing a theoretical foundation for innovative therapeutic strategies.
|
