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小胶质细胞氧化磷酸化和吞噬作用的升高可刺激中风后小鼠的大脑重塑和认知功能恢复。

Elevated microglial oxidative phosphorylation and phagocytosis stimulate post-stroke brain remodeling and cognitive function recovery in mice.

机构信息

Dept. of Neurology, Univ. of Pittsburgh, Pittsburgh, PA, USA.

Pittsburgh Institute for Neurodegenerative Disorders, Univ. of Pittsburgh, Pittsburgh, PA, USA.

出版信息

Commun Biol. 2022 Jan 11;5(1):35. doi: 10.1038/s42003-021-02984-4.

DOI:10.1038/s42003-021-02984-4
PMID:35017668
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8752825/
Abstract

New research shows that disease-associated microglia in neurodegenerative brains present features of elevated phagocytosis, lysosomal functions, and lipid metabolism, which benefit brain repair. The underlying mechanisms remain poorly understood. Intracellular pH (pH) is important for regulating aerobic glycolysis in microglia, where Na/H exchanger (NHE1) is a key pH regulator by extruding H in exchange of Na influx. We report here that post-stroke Cx3cr1-Cre;Nhe1 (Nhe1 cKO) brains displayed stimulation of microglial transcriptomes of rate-limiting enzyme genes for glycolysis, tricarboxylic acid cycle, and oxidative phosphorylation. The other upregulated genes included genes for phagocytosis and LXR/RXR pathway activation as well as the disease-associated microglia hallmark genes (Apoe, Trem2, Spp1). The cKO microglia exhibited increased oxidative phosphorylation capacity, and higher phagocytic activity, which likely played a role in enhanced synaptic stripping and remodeling, oligodendrogenesis, and remyelination. This study reveals that genetic blockade of microglial NHE1 stimulated oxidative phosphorylation immunometabolism, and boosted phagocytosis function which is associated with tissue remodeling and post-stroke cognitive function recovery.

摘要

新研究表明，神经退行性脑疾病相关的小胶质细胞表现出吞噬作用、溶酶体功能和脂质代谢升高的特征，这有利于大脑修复。其潜在机制仍知之甚少。细胞内 pH（pH）对于调节小胶质细胞的有氧糖酵解很重要，其中 Na/H 交换器（NHE1）通过排出 H 并交换 Na 内流来作为关键的 pH 调节剂。我们在此报告，中风后 Cx3cr1-Cre;Nhe1（Nhe1 cKO）大脑显示出糖酵解、三羧酸循环和氧化磷酸化限速酶基因的小胶质细胞转录组受到刺激。其他上调的基因包括吞噬作用和 LXR/RXR 通路激活以及与疾病相关的小胶质细胞特征基因（Apoe、Trem2、Spp1）。cKO 小胶质细胞表现出增强的氧化磷酸化能力和更高的吞噬活性，这可能在增强突触剥离和重塑、少突胶质细胞生成和髓鞘形成中发挥作用。这项研究揭示了小胶质细胞 NHE1 的遗传阻断刺激了氧化磷酸化免疫代谢，并增强了吞噬作用功能，这与组织重塑和中风后认知功能恢复有关。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3517/8752825/6917d38a5e7c/42003_2021_2984_Fig8_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3517/8752825/6b2d05e81cdd/42003_2021_2984_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3517/8752825/6917d38a5e7c/42003_2021_2984_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3517/8752825/b24e62b7fc43/42003_2021_2984_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3517/8752825/efd7d049eb7b/42003_2021_2984_Fig2_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3517/8752825/c8cbe3802351/42003_2021_2984_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3517/8752825/8972fac91d26/42003_2021_2984_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3517/8752825/4d83cb074e4b/42003_2021_2984_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3517/8752825/6b2d05e81cdd/42003_2021_2984_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3517/8752825/6917d38a5e7c/42003_2021_2984_Fig8_HTML.jpg

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