Zou Chenming, Cai Ruihua, Li Yunbing, Xue Yu, Zhang Guoguang, Alitongbieke Gulimiran, Pan Yutian, Zhang Sanguo
The Engineering Technological Center of Mushroom Industry, Minnan Normal University, Zhangzhou 363000, China.
Fujian Fungal Active Substance Engineering Technology Center, Zhangzhou 363000, China.
iScience. 2024 Aug 20;27(9):110766. doi: 10.1016/j.isci.2024.110766. eCollection 2024 Sep 20.
Recently, increasing evidence has shown the association between liver abnormal inflammation and cognition impairment, yet their age-related pathogenesis remains obscure. Here, our study provides a potential mechanistic link between liver macrophage excessive activation and neuroinflammation in aging progression. In aged and LPS-injected C57BL/6J mice, systemic administration of β-chitosan ameliorates hepatic macrophage-driven inflammation and reduces peripheral accumulations of TNF-α and IL-1β. Downregulation of circulatory pro-inflammatory cytokines then decreases vascular VCAM1 expression and neuroinflammation in the hippocampus, leading to cognitive improvement in aged/LPS-stimulated mice. Interestingly, β-chitosan treatment also exhibits the beneficial effects on the behavioral recovery of aged/LPS-stimulated zebrafish and . In our cell culture and molecular docking experiments, we found that β-chitosan prefers shielding the MD-2 pocket, thus blocking the activation of TLR4-MD-2 complex to suppress NF-κB signaling pathway activation. Together, our findings highlight the extensive therapeutic potential of β-chitosan in reversing aged-related/LPS-induced cognitive impairment via the liver-brain axis.
最近，越来越多的证据表明肝脏异常炎症与认知障碍之间存在关联，但其与年龄相关的发病机制仍不清楚。在这里，我们的研究揭示了衰老过程中肝脏巨噬细胞过度活化与神经炎症之间潜在的机制联系。在老年和注射脂多糖（LPS）的C57BL/6J小鼠中，全身性给予β-壳聚糖可改善肝脏巨噬细胞驱动的炎症，并减少TNF-α和IL-1β的外周蓄积。循环促炎细胞因子的下调进而降低血管细胞黏附分子1（VCAM1）的表达以及海马体中的神经炎症，从而改善老年/LPS刺激小鼠的认知能力。有趣的是，β-壳聚糖治疗对老年/LPS刺激的斑马鱼的行为恢复也具有有益作用。在我们的细胞培养和分子对接实验中，我们发现β-壳聚糖倾向于遮蔽MD-2口袋，从而阻断TLR4-MD-2复合物的活化，抑制NF-κB信号通路的激活。总之，我们的研究结果突出了β-壳聚糖通过肝脑轴逆转衰老相关/LPS诱导的认知障碍的广泛治疗潜力。
