GSK-3β inhibitors suppressed neuroinflammation in rat cortex by activating autophagy in ischemic brain injury

Zhao, Xiaogang; Zhou, Jian; Li, Xilei; Guo, Changan; Fang, Taolin; Chen, Zhengrong

doi:10.1016/j.bbrc.2011.06.117

Cited by 90 publications

(65 citation statements)

References 28 publications

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“…Recently, induction of autophagy by GSK3B inhibitors has been shown to decrease neuroinflammation following ischemic brain injury. 52 We hypothesize that restoration of autophagy flux may also attenuate inflammatory responses after TBI.…”

Section: Discussionmentioning

confidence: 99%

Impaired autophagy flux is associated with neuronal cell death after traumatic brain injury

et al. 2014

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Keywords: autophagy, autophagy flux, lysosome, neuronal cell death, traumatic brain injury Abbreviations: ACTB, actin; b; AIF1/IBA1, allograft inflammatory factor 1; AIFM1, apoptosis-inducing factor, mitochondrion-associated, 1; APC, adenomatous polyposis coli; ATG12, autophagy-related 12; ATG5, autophagy-related 5; ATG7, autophagy-related 7; CAPS12, caspase 12; CASP3, caspase 3; CCI, controlled cortical impact; CD68, CD68 molecule; CSPG4, chondroitin sulfate proteoglycan 4; CTSD, cathepsin D; GFP, green fluorescent protein; LAMP1, lysosomal-associated membrane protein 1; LAMP2, lysosomal-associated membrane protein 2; LC3, microtubule associated protein 1 light chain 3; RBFOX3, RNA binding protein, fox-1 homolog (C. elegans) 3; SPTAN1, spectrin, a, non-erythrocytic 1; SQSTM1, sequestosome 1; TBI, traumatic brain injury; ULK1, unc-51 like autophagy activating kinase 1.Dysregulation of autophagy contributes to neuronal cell death in several neurodegenerative and lysosomal storage diseases. Markers of autophagy are also increased after traumatic brain injury (TBI), but its mechanisms and function are not known. Following controlled cortical impact (CCI) brain injury in GFP-Lc3 (green fluorescent protein-LC3) transgenic mice, we observed accumulation of autophagosomes in ipsilateral cortex and hippocampus between 1 and 7 d. This accumulation was not due to increased initiation of autophagy but rather to a decrease in clearance of autophagosomes, as reflected by accumulation of the autophagic substrate SQSTM1/p62 (sequestosome 1). This was confirmed by ex vivo studies, which demonstrated impaired autophagic flux in brain slices from injured as compared to control animals. Increased SQSTM1 peaked at d 1-3 but resolved by d 7, suggesting that the defect in autophagy flux is temporary. The early impairment of autophagy is at least in part caused by lysosomal dysfunction, as evidenced by lower protein levels and enzymatic activity of CTSD (cathepsin D). Furthermore, immediately after injury both autophagosomes and SQSTM1 accumulated predominantly in neurons. This was accompanied by appearance of SQSTM1 and ubiquitin-positive puncta in the affected cells, suggesting that, similar to the situation observed in neurodegenerative diseases, impaired autophagy may contribute to neuronal injury. Consistently, GFP-LC3 and SQSTM1 colocalized with markers of both caspase-dependent and caspase-independent cell death in neuronal cells proximal to the injury site. Taken together, our data indicated for the first time that autophagic clearance is impaired early after TBI due to lysosomal dysfunction, and correlates with neuronal cell death.

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Section: Discussionmentioning

confidence: 99%

Impaired autophagy flux is associated with neuronal cell death after traumatic brain injury

et al. 2014

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“…The dopamine system also regulates lymphocyte activity in lupus and MS, suggesting an important role of dopamine in the regulation of peripheral or CNS infi ltrated lymphocytes during the pathogenesis of MS [64,65] . In addition, inhibition of neuro-infl ammation by autophagy has great benefi ts on ischemia [66] . Autophagy may be a stress response to the negative feedback regulation of neuro-infl ammation.…”

Section: Autophagy and Neuro-infl Ammationmentioning

confidence: 99%

Role of autophagy in the pathogenesis of multiple sclerosis

Liang

2015

Neurosci. Bull.

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Autophagy plays an important role in maintaining the cellular homeostasis. One of its functions is to degrade unnecessary organelles and proteins for energy recycling or amino-acids for cell survival. Ablation of autophagy leads to neurodegeneration. Multiple sclerosis (MS), a permanent neurological impairment typical of chronic inflammatory demyelinating disorder, is an auto-immune disease of the central nervous system (CNS). Autophagy is tightly linked to the innate and adaptive immune systems during the autoimmune process, and several studies have shown that autophagy directly participates in the progress of MS or experimental autoimmune encephalomyelitis (EAE, a mouse model of MS). Dysfunction of mitochondria that intensively infl uences the autophagy pathway is one of the important factors in the pathogenesis of MS. Autophagy-related gene (ATG) 5 and immune-related GTPase M (IRGM) 1 are increased, while ATG16L2 is decreased, in T-cells in EAE and active relapsing-remitting MS brains. Administration of rapamycin, an inhibitor of mammalian target of rapamycin ( mTOR), ameliorates relapsing-remitting EAE. Infl ammation and oxidative stress are increased in MS lesions and EAE, but Lamp2 and the LC3-II/LC3-I ratio are decreased. Furthermore, autophagy in various glial cells plays important roles in regulating neuro-infl ammation in the CNS, implying potential roles in MS. In this review, we discuss the role of autophagy in the peripheral immune system and the CNS in neuroinfl ammation associated with the pathogenesis of MS. Keywords: autophagy; multiple sclerosis; neuro-infl ammation ·Review· IntroductionAutophagy, a lysosome-dependent degradation pathway, contributes to maintaining cellular homeostasis. Clearance of long-lived proteins, unnecessary organelles, and aggregate-prone proteins is mainly executed by autophagy for recycling cellular materials [1] . There are three subtypes of autophagy, macroautophagy, chaperone-mediated autophagy (CMA), and mitophagy. Macroautophagy is the major type for selective degradation of protein aggregates or misfolded proteins. The ubiquitin-labeled proteins are recognized by autophagy receptors, such as p62, neighbor of BRCA1 gene 1 (NBR1), and NIP3-like protein X (NIX), to form autophagosomes that then fuse with lysosomes for degradation. Many autophagy-related genes function during this process, such as Unc51-like kinase (ULK1) and autophagy-related gene (ATG) 5. Mammalian target of rapamycin (mTOR) represses autophagy by regulating ULK1 phosphorylation, while AMPK activates this process.CMA mediates the degradation of large molecular-weight proteins containing the KFERQ motif recognized by heat shock cognate protein of 70 kDa (HSC70). The substrate is then escorted to lysosome-associated membrane protein 2 (LAMP2A) for lysosomal degradation. Mitophagy is responsible for the degradation of damaged mitochondria.Parkin and PINK1 play critical roles in this process [2] . More Neurosci Bull August 1, 2015, 31(4): 435-444 436 attention has been paid to autophagy in the path...

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“…149 Along these lines, recent studies have demonstrated that autophagy negatively regulates inflammatory response, protecting cells from ischemic brain injury and endotoxin-induced intestinal epithelium injury. 152,153 Further research is needed to gain insights into underlying mechanisms for the renoprotection of tubular cell autophagy in AKI.…”

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confidence: 99%

Emerging role of autophagy in kidney function, diseases and aging

et al. 2012

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Autophagy is a highly conserved process that degrades cellular long-lived proteins and organelles. Accumulating evidence indicates that autophagy plays a critical role in kidney maintenance, diseases and aging. Ischemic, toxic, immunological, and oxidative insults can cause an induction of autophagy in renal epithelial cells modifying the course of various kidney diseases. This review summarizes recent insights on the role of autophagy in kidney physiology and diseases alluding to possible novel intervention strategies for treating specific kidney disorders by modifying autophagy.

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GSK-3β inhibitors suppressed neuroinflammation in rat cortex by activating autophagy in ischemic brain injury

Cited by 90 publications

References 28 publications

Impaired autophagy flux is associated with neuronal cell death after traumatic brain injury

Impaired autophagy flux is associated with neuronal cell death after traumatic brain injury

Role of autophagy in the pathogenesis of multiple sclerosis

Emerging role of autophagy in kidney function, diseases and aging

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