Sex differences in the neuroinflammatory signaling pathway: effect of miRNAs on fatty acid synthesis in microglia.

IF 4.9 2区 医学 Q1 ENDOCRINOLOGY & METABOLISM
Haolin Zheng, Akiko Mizokami, Sergio Romera-Giner, Jaime Llera-Oyola, Yosuke Yamawaki, Tomomi Sano, Eijiro Jimi, Francisco García-García, Takashi Kanematsu
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引用次数: 0

Abstract

Background: Significant sex differences exist in the prevalence and incidence of Alzheimer's disease (AD). Notably, testosterone has been reported to regulate cognitive functions in the brain, with low serum testosterone levels correlating with increased AD risk. However, the specific mechanisms underlying this relationship remain unclear. Recent studies have demonstrated that microglia, the primary innate immune cells in the brain, play a crucial role in AD development. Therefore, this study aimed to explore sex differences in microglial function, specifically focusing on the role of testosterone in miRNA-mediated regulation of microglial gene expression.

Methods: Microglia were isolated from pooled hippocampal tissue of five 8-month-old male and female mice. Total RNA was extracted and subjected to miRNA microarray analysis. The mouse microglial cell line MG6 was used for in vitro experiments. Following testosterone treatment, miRNA, gene, and protein expression levels were investigated. An inflammatory response was induced using lipopolysaccharide (LPS) stimulation, and subsequent p65 phosphorylation was assessed.

Results: Sex-dependent differences were observed in miRNA-mediated biological processes, with males exhibiting greater changes. Male-enriched miRNAs were associated with fatty acid synthesis and metabolism pathways. In MG6 cells, testosterone treatment upregulated the expression of several miRNAs enriched in male microglia, particularly those targeting genes related to fatty acid synthesis. Additionally, testosterone significantly reduced the gene expression of fatty acid synthase (FASN). This testosterone-induced inhibition of FASN expression attenuated NF-κB/p65 phosphorylation. Consequently, the suppression of FASN expression led to reduced expression and secretion of tumor necrosis factor-alpha following LPS stimulation in MG6 cells.

Conclusions: These findings suggest that testosterone modulates inflammation in male microglia by regulating fatty acid synthesis, potentially contributing to the observed sex differences in AD pathogenesis.

神经炎症信号通路的性别差异:miRNA 对小胶质细胞脂肪酸合成的影响。
背景:阿尔茨海默病(AD)的患病率和发病率存在显著的性别差异。值得注意的是,据报道,睾酮可以调节大脑的认知功能,血清睾酮水平低与阿尔茨海默病风险增加有关。然而,这种关系背后的具体机制尚不清楚。最近的研究表明,小胶质细胞是大脑中主要的先天免疫细胞,在阿尔茨海默病的发展中起着至关重要的作用。因此,本研究旨在探讨小胶质细胞功能的性别差异,特别关注睾酮在mirna介导的小胶质细胞基因表达调控中的作用。方法:从5只8月龄雌雄小鼠海马组织中分离小胶质细胞。提取总RNA并进行miRNA芯片分析。采用小鼠小胶质细胞系MG6进行体外实验。睾酮治疗后,观察miRNA、基因和蛋白表达水平。使用脂多糖(LPS)刺激诱导炎症反应,并评估随后的p65磷酸化。结果:在mirna介导的生物学过程中存在性别差异,男性变化更大。男性富集的mirna与脂肪酸合成和代谢途径相关。在MG6细胞中,睾酮处理上调了男性小胶质细胞中富集的几种mirna的表达,特别是那些针对脂肪酸合成相关基因的mirna。此外,睾酮显著降低脂肪酸合成酶(FASN)的基因表达。这种睾酮诱导的FASN表达抑制减弱了NF-κB/p65的磷酸化。因此,抑制FASN表达导致LPS刺激后MG6细胞中肿瘤坏死因子- α的表达和分泌减少。结论:这些发现表明睾酮通过调节脂肪酸合成来调节男性小胶质细胞的炎症,这可能是AD发病机制中观察到的性别差异的原因。
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来源期刊
Biology of Sex Differences
Biology of Sex Differences ENDOCRINOLOGY & METABOLISM-GENETICS & HEREDITY
CiteScore
12.10
自引率
1.30%
发文量
69
审稿时长
14 weeks
期刊介绍: Biology of Sex Differences is a unique scientific journal focusing on sex differences in physiology, behavior, and disease from molecular to phenotypic levels, incorporating both basic and clinical research. The journal aims to enhance understanding of basic principles and facilitate the development of therapeutic and diagnostic tools specific to sex differences. As an open-access journal, it is the official publication of the Organization for the Study of Sex Differences and co-published by the Society for Women's Health Research. Topical areas include, but are not limited to sex differences in: genomics; the microbiome; epigenetics; molecular and cell biology; tissue biology; physiology; interaction of tissue systems, in any system including adipose, behavioral, cardiovascular, immune, muscular, neural, renal, and skeletal; clinical studies bearing on sex differences in disease or response to therapy.
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