Troxerutin dampened hypothalamic neuroinflammation via microglial IL-22/IL-22R1/IRF3 activation in dihydrotestosterone-induced polycystic ovary syndrome rats

被引:6
作者
Gao, Zixuan [1 ,3 ]
Tan, Huihui [1 ]
Song, Xueli [1 ]
Zhuang, Tao [1 ]
Kong, Renyu [1 ]
Wang, Yuying [3 ]
Yan, Xiaonan [2 ]
Yao, Ruiqin [1 ]
机构
[1] Xuzhou Med Univ, Xuzhou Key Lab Neurobiol, Dept Cell Biol & Neurobiol, 209 Tongshan Rd, Xuzhou 221009, Jiangsu, Peoples R China
[2] Xuzhou Med Univ, Xuzhou Cent Hosp, Xuzhou Clin Sch, Clin Ctr Reprod Med, 199 Jiefang South Rd, Xuzhou 221000, Peoples R China
[3] Xuzhou Med Univ, Affiliated Hosp 3, Dept Gynaecol & Obstet, 388 Fuxing South Rd, Xuzhou 221000, Peoples R China
基金
中国国家自然科学基金;
关键词
Polycystic ovary syndrome; Interleukin-22; Troxerutin; Interferon regulatory factor3; Microglia M1/2 polarization; EXPRESSION; INTERLEUKIN-22; ETIOLOGY; CELLS;
D O I
10.1016/j.phymed.2023.155280
中图分类号
Q94 [植物学];
学科分类号
071001 ;
摘要
Background: Polycystic ovary syndrome (PCOS) is the most common reproductive-endocrine condition in premenopausal women. Troxerutin, a common clinical anti-coagulant agent, was shown to work as a strong IL-22 boosting agent counteracting the hyperactivated gonadotrophin releasing hormone (GnRH) neurons and heightened GnRH release, the neuroendocrine origin of PCOS with unknown mechanism in rats. Exploring the off-label use of troxerutin medication for PCOS is thus sorely needed. Methods: Serum IL-22 content and hypothalamic IL-22 protein were detected. Inflammatory factor levels in hypothalamo-pituitary were evaluated. Immunofluorescence staining was employed to determine the activation and M1/M2-prone polarization of microglia in arcuate hypothalamus and median eminence. RNA-sequencing and transcriptome analysis were applied to explore the potential driver of microglia M2-polarization in response to IL-22 bolstering effect. The function of microglial IL-22/IL-22R1/IRF3 system was further verified using in vivo knockdown of IL-22R1 and a potent IRF3 inhibitor in BV2 microglial cell lines in vitro. Results: Troxerutin augmented serum IL-22 content, and its consequent spillover into the hypothalamus led to the direct activation of IL-22R1/IRF3 system on microglia, thereby promoted microglia M2 polarization in arcuate hypothalamus and median eminence, dampened hypothalamic neuroinflammation, inhibited hyperactive GnRH and rescued a breadth of PCOS-like traits in dihydrotestosterone (DHT) rats. The salutary effects of troxerutin treatment on hypothalamic neuroinflammation, microglial M1/2 polarization, GnRH secretion and numerous PCOS-like features were blocked by in vivo knockdown of IL-22R1. Moreover, evidence in vitro illustrated that IL22 supplement to BV-2 microglia cell lines promoted M2 polarization, overproduction of anti-inflammatory marker and limitation of pro-inflammatory factors, whereas these IL-22 effects were blunted by geldanamycin, a potent IRF3 inhibitor. Conclusion: Here, the present study reported the potential off-label use of troxerutin medication, a common clinical anti-coagulant agent and an endogenous IL-22 enhancer, for multiple purposes in PCOS. The rational underlying the application of troxerutin as a therapeutic choice in PCOS derived from its activity as an IL-22 memetic agent targeting the neuro-endocrine origin of PCOS, and its promotive impact on microglia M2 polarization via activating microglial IL-22R1/IRF3 system in the arcuate hypothalamus and median eminence of DHT female rats.
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页数:15
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