Bilirubin impacts microglial autophagy via the Akt-mTOR signaling pathway

作者全名："Li, Ling; Li, Siyu; Pan, Zhifan; Zhang, Yan; Hua, Ziyu"

作者地址："[Li, Ling; Li, Siyu; Hua, Ziyu] Chongqing Med Univ, Natl Clin Res Ctr Child Hlth & Disorders, Key Lab Child Dev & Disorders, Dept Neonatol,Childrens Hosp,Minist Educ, Chongqing, Peoples R China; [Li, Ling; Li, Siyu; Pan, Zhifan; Zhang, Yan; Hua, Ziyu] China Int Sci & Technol, Cooperat Base Child Dev & Crit Disorders, Chongqing, Peoples R China; [Li, Ling; Li, Siyu; Pan, Zhifan; Zhang, Yan] Chongqing Key Lab Child Infect & Immun, Chongqing, Peoples R China; [Hua, Ziyu] Chongqing Med Univ, Dept Neonatol, Childrens Hosp, Chongqing 400014, Peoples R China"

通信作者："Hua, ZY (通讯作者)，Chongqing Med Univ, Dept Neonatol, Childrens Hosp, Chongqing 400014, Peoples R China."

来源：JOURNAL OF NEUROCHEMISTRY

ESI学科分类：NEUROSCIENCE & BEHAVIOR

WOS号：WOS:001085538600001

JCR分区：Q2

影响因子：4.2

年份：2023

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：autophagy; bilirubin; microglia; neuroinflammation

摘要："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-1 beta, 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"

基金机构：All experiments were conducted in compliance with the ARRIVE guidelines.

基金资助正文："This research was supported by the National Natural Science Foundation of China (Grant No. 81971426) and the Postgraduate Research Innovation Project of Chongqing (Grant No. CYS21227 and CYB22213), the Key Project for Technological Innovation and Application Development of Chongqing (Grant No. CSTB2022TIAD-KPX0147) and the Science and Technology Research Program of Chongqing Education Commission (Grant No. KJZD-M202300403).r All experiments were conducted in compliance with the ARRIVE guidelines."