Bilirubin impacts microglial autophagy via the Akt–mTOR signaling pathway
Bilirubin impacts microglial autophagy via the Akt–mTOR signaling pathway
复制标题
胆红素通过Akt-mTOR信号通路影响小胶质细胞自噬
DOI：
10.1111/jnc.15984
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发表时间：
2023-10
影响因子：
4.7
通讯作者：
Ling Li;Siyu Li;Zhifan Pan;Yan Zhang;Ziyu Hua
中科院分区：
文献类型：
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作者：
Ling Li;Siyu Li;Zhifan Pan;Yan Zhang;Ziyu Hua
胆红素脑病是新生儿高胆红素血症的严重并发症。随着血清非共轭胆红素（UCB）水平的升高，UCB穿过血脑屏障，可能导致神经功能障碍。神经炎症被认为是胆红素脑病的一个突出的病理特征。最近的研究表明，自噬在炎症反应中起着至关重要的作用。然而，小胶质细胞自噬在胆红素脑病发病机制中的潜在作用仍不确定。体外实验结果证实，在原代培养的小胶质细胞中，UCB显著降低LC3B‐II与LC3B‐I的比例，下调ATG5、Beclin‐1和ATG7的表达，同时增加p62/SQSTM1的表达。结果表明，即使使用氯喹（chloroquine， CQ）阻断小胶质细胞自噬通量，UCB也能减少mCherry‐EGFP‐LC3阳性点的数量。从机制上看，UCB上调TLR4的表达，增加Akt和哺乳动物雷帕霉素靶蛋白（mTOR）的磷酸化水平。用mTOR抑制剂雷帕霉素（Rapamycin， RAPA）治疗可促进小胶质细胞自噬，降低NOD样受体蛋白3 （NLRP3）炎性体成分和IL - 1β的水平，挽救小胶质细胞过度活化，改善神经功能。这些数据表明UCB可以通过Akt-mTOR信号通路影响小胶质细胞自噬，并协同促进神经炎症反应。增强自噬可能破坏NLRP3炎性体的组装，减轻UCB诱导的神经炎症，改善胆红素脑病模型大鼠的预后。总之，本研究提示调节小胶质细胞自噬可能是治疗胆红素脑病的一种有希望的治疗策略。
Bilirubin encephalopathy is a severe complication of neonatal hyperbilirubinemia. With elevation of serum unconjugated bilirubin (UCB) levels, UCB crosses the blood–brain barrier and possibly leads to neurological dysfunction. Neuroinflammation is recognized as a prominent pathological feature in bilirubin encephalopathy. Recent studies have suggested that autophagy plays a crucial role in the inflammatory response. However, the potential effect of microglial autophagy in the pathogenesis of bilirubin encephalopathy remains uncertain. The in vitro findings verified that in primary cultured microglia, UCB significantly reduced the ratio of LC3B‐II to LC3B‐I and downregulated the expression of ATG5, Beclin‐1, and ATG7, while increasing the expression of p62/SQSTM1. The results showed that UCB could decrease the number of mCherry‐EGFP‐LC3 positive puncta, even when chloroquine (CQ) was applied to block the microglial autophagy flux. Mechanistically, UCB was found to upregulate the expression of TLR4 and increase the phosphorylation levels of Akt and mammalian target of rapamycin (mTOR). Promoting microglial autophagy by treatment with Rapamycin (RAPA), an mTOR inhibitor, decreased the levels of NOD‐like receptor protein 3 (NLRP3) inflammasome components and IL‐1β, rescued microglial overactivation, and improved neurological functions. These data indicated that UCB could impact microglial autophagy via the Akt–mTOR signaling pathway and synergistically promote neuroinflammatory responses. Enhancing autophagy might disrupt the assembly of NLRP3 inflammasome, attenuate UCB‐induced neuroinflammation, and improve the prognosis of model rats with bilirubin encephalopathy. In conclusion, this study implies that regulating microglial autophagy might be a promising therapeutic strategy for bilirubin encephalopathy.