背景：槲皮素因其治疗呼吸道合胞病毒（RSV）感染疾病的潜力而受到广泛关注。最近的研究强调了槲皮素抑制肺泡巨噬细胞（AMs）衍生的肺部炎症的能力。然而,槲皮素对RSV感染的抗炎作用机制尚不清楚。
目的：本研究旨在阐明槲皮素对RSV感染的抗炎作用机制。
方法：BALB/c小鼠鼻内感染RSV，口服槲皮素（30、60、120mg/kg/d）3天。此外,利用小鼠肺泡巨噬细胞(MH-S细胞)的体外感染模型被用来验证所提出的机制.
结果：槲皮素对RSV感染的AMs的糖酵解和三羧酸（TCA）循环代谢表现出下调作用。然而，它增加了衣康酸的产量，通过激活免疫反应基因1（IRG1）从柠檬酸盐衍生的代谢物，并进一步抑制琥珀酸脱氢酶(SDH)活性。虽然SDH活性的抑制协调了Hif-1α/NLRP3信号的级联下调，最终导致从M1到M2表型的AM极化。
结论：我们的研究表明槲皮素刺激IRG1介导的衣康酸合成代谢，并进一步抑制SDH/Hif-1α/NLRP3信号通路，这导致AMs的M1到M2极化，从而改善RSV诱导的肺部炎症。
BACKGROUND: Quercetin has received extensive attention for its therapeutic potential treating respiratory syncytial virus (RSV) infection diseases. Recent studies have highlighted quercetin\'s ability of suppressing alveolar macrophages (AMs)-derived lung inflammation. However, the anti-inflammatory mechanism of quercetin against RSV infection still remains elusive.
OBJECTIVE: This study aims to elucidate the mechanism about quercetin anti-inflammatory effect on RSV infection.
METHODS: BALB/c mice were intranasally infected with RSV and received quercetin (30, 60, 120 mg/kg/d) orally for 3 days. Additionally, an in vitro infection model utilizing mouse alveolar macrophages (MH-S cells) was employed to validate the proposed mechanism.
RESULTS: Quercetin exhibited a downregulatory effect on glycolysis and tricarboxylic acid (TCA) cycle metabolism in RSV-infected AMs. However, it increased itaconic acid production, a metabolite derived from citrate through activating immune responsive gene 1 (IRG1), and further inhibiting succinate dehydrogenase (SDH) activity. While the suppression of SDH activity orchestrated a cascading downregulation of Hif-1α/NLRP3 signaling, ultimately causing AMs polarization from M1 to M2 phenotypes.
CONCLUSIONS: Our study demonstrated quercetin stimulated IRG1-mediated itaconic acid anabolism and further inhibited SDH/Hif-1α/NLRP3 signaling pathway, which led to M1 to M2 polarization of AMs so as to ameliorate RSV-induced lung inflammation.
