Department of Nutrition and Food Science, University of Maryland, College Park, MD, United States.
Department of Periodontology and Oral Biology, College of Dentistry, University of Florida, Gainesville, FL, United States.
Front Immunol. 2024 Sep 30;15:1437540. doi: 10.3389/fimmu.2024.1437540. eCollection 2024.
Persistent inflammation is a major contributor in the development of various inflammatory diseases like atherosclerosis. Our study investigates how transient receptor potential vanilloid 4 (TRPV4), a mechanosensitive ion channel, interacts with microRNA-146a (miR-146a), within the context of inflammation and atherosclerosis. Micro-RNAs play a critical role in controlling gene expression, and miR-146a is notable for its anti-inflammatory actions. TRPV4 is activated by diverse soluble and mechanical stimuli, and often associated with inflammatory responses in various diseases. Here, we find that TRPV4 negatively regulates miR-146a expression in macrophages, especially following stimulation by lipopolysaccharides or alterations in matrix stiffness. We show that in atherosclerosis, a condition characterized by matrix stiffening, TRPV4 decreases miR-146a expression in aortic tissue macrophages. We find that TRPV4's impact on miR-146a is independent of activation of NFκB, Stat1, P38, and AKT, but is rather mediated through a mechanism involving histone deacetylation instead of DNA methylation at the miR-146a promoter site. Furthermore, we show that N-terminal residues 1 to 130 in TRPV4 is essential in suppression of miR-146a expression in LPS-stimulated macrophages. Altogether, this study identifies a regulatory mechanism of miR-146a expression by TRPV4 which may open new potential therapeutic strategies for managing inflammatory diseases.
持续性炎症是各种炎症性疾病（如动脉粥样硬化）发展的主要因素。我们的研究调查了瞬时受体电位香草醛 4（TRPV4），一种机械敏感的离子通道，如何在炎症和动脉粥样硬化的背景下与 microRNA-146a（miR-146a）相互作用。microRNAs 在控制基因表达方面起着关键作用，而 miR-146a 以其抗炎作用而闻名。TRPV4 被多种可溶性和机械刺激激活，并且通常与各种疾病中的炎症反应有关。在这里，我们发现 TRPV4 在巨噬细胞中负调节 miR-146a 的表达，特别是在受到脂多糖或基质硬度变化刺激后。我们表明，在动脉粥样硬化中，一种以基质变硬为特征的疾病，TRPV4 会降低主动脉组织巨噬细胞中 miR-146a 的表达。我们发现 TRPV4 对 miR-146a 的影响独立于 NFκB、Stat1、P38 和 AKT 的激活，而是通过一种涉及组蛋白去乙酰化而不是 miR-146a 启动子位点的 DNA 甲基化的机制介导的。此外，我们表明 TRPV4 的 N 端残基 1 到 130 对于抑制 LPS 刺激的巨噬细胞中 miR-146a 的表达是必需的。总之，这项研究确定了 TRPV4 对 miR-146a 表达的调节机制，这可能为管理炎症性疾病开辟新的潜在治疗策略。
