Luo Doudou, Ye Wenxuan, Chen Ling, Yuan Xiaoqian, Zhang Yali, Chen Caixia, Jin Xin, Zhou Yu
Department of Basic Medical Science, School of Medicine, Xiamen University, Xiamen 361102, China.
Key Laboratory of Chiral Drugs, Xiamen 361102, China.
Biomedicines. 2023 Mar 21;11(3):973. doi: 10.3390/biomedicines11030973.
Astrocyte inflammation activation is an important cause that hinders the recovery of motor function after cerebral ischemia. However, its molecular mechanism has not yet been clearly clarified. The peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated nuclear transcriptional factor. This study aims to further clarify the role of PPARα in astrocyte inflammation activation after cerebral ischemia and to explore the underlying mechanism. Astrocyte activation was induced in an in vivo model by transient middle cerebral artery occlusion (tMCAO) in mice. The in vitro model was induced by an oxygen-glucose deprivation/reoxygenation (OGD/R) in a primary culture of mouse astrocyte. PPARα-deficient mice were used to observe the effects of PPARα on astrocyte activation and autophagic flux. Our results showed that PPARα was mainly expressed in activated astrocytes during the chronic phase of brain ischemia and PPARα dysfunction promoted astrocyte inflammatory activation. After cerebral ischemia, the expressions of LC3-II/I and p62 both increased. Autophagic vesicle accumulation was observed by electron microscopy in astrocytes, and the block of autophagic flux was indicated by an mRFP-GFP-LC3 adenovirus infection assay. A PPARα deficit aggravated the autophagic flux block, while PPARα activation preserved the lysosome function and restored autophagic flux in astrocytes after OGD/R. The autophagic flux blocker bafilomycin A1 and chloroquine antagonized the effect of the PPARα agonist on astrocyte activation inhibition. This study identifies a potentially novel function of PPARα in astrocyte autophagic flux and suggests a therapeutic target for the prevention and treatment of chronic brain ischemic injury.
星形胶质细胞炎症激活是阻碍脑缺血后运动功能恢复的重要原因。然而，其分子机制尚未完全阐明。过氧化物酶体增殖物激活受体α（PPARα）是一种配体激活的核转录因子。本研究旨在进一步阐明PPARα在脑缺血后星形胶质细胞炎症激活中的作用，并探讨其潜在机制。通过小鼠短暂性大脑中动脉闭塞（tMCAO）在体内模型中诱导星形胶质细胞激活。在小鼠星形胶质细胞原代培养中通过氧糖剥夺/复氧（OGD/R）诱导体外模型。使用PPARα缺陷小鼠观察PPARα对星形胶质细胞激活和自噬通量的影响。我们的结果表明，PPARα在脑缺血慢性期主要表达于活化的星形胶质细胞中，PPARα功能障碍促进星形胶质细胞炎症激活。脑缺血后，LC3-II/I和p62的表达均增加。通过电子显微镜在星形胶质细胞中观察到自噬泡积累，mRFP-GFP-LC3腺病毒感染试验表明自噬通量受阻。PPARα缺陷加剧了自噬通量阻滞，而PPARα激活可保留溶酶体功能并恢复OGD/R后星形胶质细胞的自噬通量。自噬通量阻断剂巴佛洛霉素A1和氯喹拮抗PPARα激动剂对星形胶质细胞激活抑制的作用。本研究确定了PPARα在星形胶质细胞自噬通量中的潜在新功能，并提出了预防和治疗慢性脑缺血损伤的治疗靶点。
