Background:Salt sensitivity of blood pressure is an independent predictor of cardiovascular morbidity and mortality. The exact mechanism by which salt intake increases blood pressure and cardiovascular risk is unknown. We previously found that sodium entry into antigen-presenting cells (APCs) via the amiloride-sensitive epithelial sodium channel EnaC (epithelial sodium channel) leads to the formation of IsoLGs (isolevuglandins) and release of proinflammatory cytokines to activate T cells and modulate salt-sensitive hypertension. In the current study, we hypothesized that ENaC-dependent entry of sodium into APCs activates the NLRP3 (NOD [nucleotide-binding and oligomerization domain]-like receptor family pyrin domain containing 3) inflammasome via IsoLG formation leading to salt-sensitive hypertension.Methods:We performed RNA sequencing on human monocytes treated with elevated sodium in vitro and Cellular Indexing of Transcriptomes and Epitopes by Sequencing analysis of peripheral blood mononuclear cells from participants rigorously phenotyped for salt sensitivity of blood pressure using an established inpatient protocol. To determine mechanisms, we analyzed inflammasome activation in mouse models of deoxycorticosterone acetate salt–induced hypertension as well as salt-sensitive mice with ENaC inhibition or expression, IsoLG scavenging, and adoptive transfer of wild-type dendritic cells into NLRP3 deficient mice.Results:We found that high levels of salt exposure upregulates the NLRP3 inflammasome, pyroptotic and apoptotic caspases, and IL (interleukin)-1β transcription in human monocytes. Cellular Indexing of Transcriptomes and Epitopes by Sequencing revealed that components of the NLRP3 inflammasome and activation marker IL-1β dynamically vary with changes in salt loading/depletion. Mechanistically, we found that sodium-induced activation of the NLRP3 inflammasome is ENaC and IsoLG dependent. NLRP3 deficient mice develop a blunted hypertensive response to elevated sodium, and this is restored by the adoptive transfer of NLRP3 replete APCs.Conclusions:These findings reveal a mechanistic link between ENaC, inflammation, and salt-sensitive hypertension involving NLRP3 inflammasome activation in APCs. APC activation via the NLRP3 inflammasome can serve as a potential diagnostic biomarker for salt sensitivity of blood pressure.

中文翻译：

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DC ENaC 依赖性炎症小体激活导致盐敏感性高血压


背景：血压的盐敏感性是心血管发病率和死亡率的独立预测因素。盐摄入增加血压和心血管风险的确切机制尚不清楚。我们之前发现，钠通过阿米洛利敏感的上皮钠通道 EnaC（上皮钠通道）进入抗原呈递细胞（APC），导致 IsoLG（异黄兰素）的形成并释放促炎细胞因子，从而激活 T 细胞并调节盐-敏感高血压。在当前的研究中，我们假设 ENaC 依赖性钠进入 APC 会通过 IsoLG 形成激活 NLRP3（NOD [核苷酸结合和寡聚化结构域]样受体家族，包含 3 吡啶结构域）炎症小体，导致盐敏感性高血压。 ：我们对体外用高钠处理的人单核细胞进行 RNA 测序，并通过使用既定的住院方案对参与者的外周血单核细胞进行测序分析，对血压的盐敏感性进行严格表型分析，并对转录组和表位进行细胞索引。为了确定机制，我们分析了醋酸脱氧皮质酮盐诱导的高血压小鼠模型以及具有 ENaC 抑制或表达的盐敏感小鼠模型中的炎症小体激活、IsoLG 清除以及将野生型树突细胞过继转移到 NLRP3 缺陷小鼠中。结果：我们发现，高水平的盐暴露会上调人类单核细胞中的 NLRP3 炎症小体、焦亡和凋亡半胱天冬酶以及 IL（白细胞介素）-1β 转录。 通过测序对转录组和表位进行细胞索引显示，NLRP3 炎性体和激活标记 IL-1β 的成分随着盐负荷/消耗的变化而动态变化。从机制上讲，我们发现钠诱导的 NLRP3 炎症小体激活是 ENaC 和 IsoLG 依赖性的。 NLRP3 缺陷小鼠对升高的钠产生迟钝的高血压反应，并且通过过继转移充满 NLRP3 的 APC 可以恢复这种反应。结论：这些发现揭示了 ENaC、炎症和盐敏感性高血压之间的机制联系，涉及 APC 中 NLRP3 炎性体的激活。通过 NLRP3 炎性体激活 APC 可以作为血压盐敏感性的潜在诊断生物标志物。