乳酸菌无细胞上清液通过 NRF2-SOD1 信号调节人类小胶质细胞的炎症和氧化应激

IF 3.6 4区 医学 Q3 CELL BIOLOGY
Mariagiovanna Di Chiano, Maria Teresa Rocchetti, Giuseppe Spano, Pasquale Russo, Caterina Allegretta, Giampaolo Milior, Raffaella Maria Gadaleta, Fabio Sallustio, Paola Pontrelli, Loreto Gesualdo, Carlo Avolio, Daniela Fiocco, Anna Gallone
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引用次数: 0

摘要

小胶质细胞是驻留在大脑中的巨噬细胞,在保护神经元方面发挥着关键作用。通过肠道-大脑轴,肠道共生微生物产生的代谢物可影响大脑功能,包括小胶质细胞的活性。核因子红细胞 2 相关因子 2(NRF2)是小胶质细胞氧化应激反应的关键调节因子,控制着细胞保护基因的表达。乳酸菌衍生的无细胞上清液(CFS)是一种后益生菌,在多项体外和体内研究中显示出抗氧化和免疫调节作用。本研究旨在探讨乳酸菌无细胞上清液在调节小胶质细胞对氧化应激和炎症反应方面的作用。在服用三种人体肠道益生菌CFS前后,HMC3小胶质细胞暴露于作为炎症诱因的脂多聚碳酸(LPS)。免疫测定和定量 RT-PCR 分别研究了 NRF2 核蛋白的活化和 NRF2 控制的抗氧化基因的表达。此外,还通过免疫测定评估了促炎和抗炎细胞因子的水平。在基础条件下和发生炎症时,所有 CFS 都会诱导 NRF2 核活性的显著增加。抗氧化基因,即血红素加氧酶 1、超氧化物歧化酶(SOD)、谷胱甘肽-S 转移酶、谷胱甘肽过氧化物酶和过氧化氢酶的转录也增加了,尤其是在炎症刺激后。此外,相对于发炎的小胶质细胞,SOD1 的活性更高。此外,对小胶质细胞进行 CFSs 预处理可降低促炎症 TNF-α 的水平,同时提高抗炎 IL-10 的水平。这些研究结果证实,肠道微生物的代谢物可在辅助小胶质细胞应对神经炎症和氧化应激方面发挥相关作用,而神经炎症和氧化应激是已知的神经退行性疾病的诱因。乳酸菌上清液中含有的代谢物可穿过肠道屏障到达中枢神经系统,并被小胶质细胞吸收。它们会诱导激活 NRF2 通路并产生炎症介质。这种相互作用可减轻两个重要事件:氧化(高水平的 NRF2)和炎症(高水平的 IL-10 和低水平的 TNF-α)。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Lactobacilli Cell-Free Supernatants Modulate Inflammation and Oxidative Stress in Human Microglia via NRF2-SOD1 Signaling

Lactobacilli Cell-Free Supernatants Modulate Inflammation and Oxidative Stress in Human Microglia via NRF2-SOD1 Signaling

Microglia are macrophage cells residing in the brain, where they exert a key role in neuronal protection. Through the gut–brain axis, metabolites produced by gut commensal microbes can influence brain functions, including microglial activity. The nuclear factor erythroid 2-related factor 2 (NRF2) is a key regulator of the oxidative stress response in microglia, controlling the expression of cytoprotective genes. Lactobacilli-derived cell-free supernatants (CFSs) are postbiotics that have shown antioxidant and immunomodulatory effects in several in vitro and in vivo studies. This study aimed to explore the effects of lactobacilli CFSs on modulating microglial responses against oxidative stress and inflammation. HMC3 microglia were exposed to lipopolysaccaride (LPS), as an inflammatory trigger, before and after administration of CFSs from three human gut probiotic species. The NRF2 nuclear protein activation and the expression of NRF2-controlled antioxidant genes were investigated by immunoassay and quantitative RT-PCR, respectively. Furthermore, the level of pro- and anti-inflammatory cytokines was evaluated by immunoassay. All CFSs induced a significant increase of NRF2 nuclear activity in basal conditions and upon inflammation. The transcription of antioxidant genes, namely heme oxygenase 1, superoxide dismutase (SOD), glutathione-S transferase, glutathione peroxidase, and catalase also increased, especially after inflammatory stimulus. Besides, higher SOD1 activity was detected relative to inflamed microglia. In addition, CFSs pre-treatment of microglia attenuated pro-inflammatory TNF-α levels while increasing anti-inflammatory IL-10 levels. These findings confirmed that gut microorganisms’ metabolites can play a relevant role in adjuvating the microglia cellular response against neuroinflammation and oxidative stress, which are known to cause neurodegenerative diseases.

Graphical Abstract

Gut-brain crosstalk: molecular point of view. Metabolites contained in the supernatant derived from Lactobacilli can cross the gut barrier and reach the central nervous system, where they are taken up by microglial cells. They induce the activation of the NRF2 pathway and the production of inflammatory mediators. This interaction attenuates two important events: oxidation (with high levels of NRF2) and inflammation (with high levels of IL-10 and low levels of TNF-α).

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来源期刊
CiteScore
7.70
自引率
0.00%
发文量
137
审稿时长
4-8 weeks
期刊介绍: Cellular and Molecular Neurobiology publishes original research concerned with the analysis of neuronal and brain function at the cellular and subcellular levels. The journal offers timely, peer-reviewed articles that describe anatomic, genetic, physiologic, pharmacologic, and biochemical approaches to the study of neuronal function and the analysis of elementary mechanisms. Studies are presented on isolated mammalian tissues and intact animals, with investigations aimed at the molecular mechanisms or neuronal responses at the level of single cells. Cellular and Molecular Neurobiology also presents studies of the effects of neurons on other organ systems, such as analysis of the electrical or biochemical response to neurotransmitters or neurohormones on smooth muscle or gland cells.
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