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Impairment of autophagy in the central nervous system during lipopolysaccharide-induced inflammatory stress in mice

机译：脂多糖诱导的小鼠炎症应激期间中枢神经系统自噬的损害

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Background Current evidence suggests a central role for autophagy in many neurodegenerative diseases including Alzheimer?s disease, Huntington?s disease, Parkinson?s disease and amyotrophic lateral sclerosis. Furthermore, it is well admitted that inflammation contributes to the progression of these diseases. Interestingly, crosstalks between autophagy and inflammation have been reported in vitro and at the peripheral level such as in Crohn?s disease. However, the impact of systemic inflammation on autophagic components in the brain remains to be documented. Therefore, this study monitored autophagy markers after acute and chronic lipopolysaccharide (LPS)-induced inflammatory stress in mice. Results We showed that acute inflammation, 24 h post-intraperitoneal 10 mg/kg LPS, substantially increased cytokine production (Interleukin(IL)-1?, Tumor necrosis factor (TNF)-? and IL-6), decreased the levels of autophagy markers (Beclin-1, p62 and LC3 II) and reduced p70S6K activation in cortex and hippocampus. In hippocampus, IL-1? levels and LC3 II expression were positively and highly correlated and a negative correlation was noted between TNF-? levels and p70S6K activation. Chronic inflammation by injection of 0.5 mg/kg LPS every three days during three months led to a moderate IL-1? production and decreased TNF-? levels. Interestingly, Beclin-1 and LC3 II levels decreased while those of p62 increased. Cortical IL-1? levels positively correlated with Beclin-1 and LC3 II and on the contrary inversely correlated with p62. Conclusion The present study is the first showing links between IL-1?-mediated inflammation and autophagy in the brain. It could open to new therapeutic strategies in brain diseases where regulation impairment of inflammation and autophagy progress with the severity of diseases.
机译：背景技术目前的证据表明自噬在许多神经退行性疾病中具有重要作用，包括阿尔茨海默氏病，亨廷顿氏病，帕金森氏病和肌萎缩性侧索硬化症。此外，众所周知，炎症促进了这些疾病的发展。有趣的是，自噬和炎症之间的串扰已在体外和外周水平如克罗恩病中报道。然而，全身性炎症对脑中自噬成分的影响尚待证明。因此，这项研究监测了急性和慢性脂多糖（LPS）诱导的小鼠炎症应激后的自噬标记。结果我们显示，腹膜内注射10 mg / kg LPS后24小时发生急性炎症，可显着增加细胞因子的产生（白介素（IL）-1α，肿瘤坏死因子（TNF）-α和IL-6），降低自噬水平标记（Beclin-1，p62和LC3 II）并降低皮层和海马中的p70S6K激活。在海马中，IL-1？水平与LC3 II表达呈正相关且高度相关，而TNF-α之间呈负相关。水平和p70S6K激活。在三个月内每三天注射一次0.5 mg / kg LPS引起的慢性炎症导致中度IL-1？产生和TNF-α降低水平。有趣的是，Beclin-1和LC3 II水平降低，而p62升高。皮质IL-1？与Beclin-1和LC3 II正相关，而与p62反相关。结论本研究首次显示了IL-1β介导的炎症与大脑自噬之间的联系。它可能对脑部疾病的新治疗策略开放，因为随着疾病的严重程度，炎症和自噬的调节障碍逐渐发展。

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