Abstract

The intracellular sensor protein complex known as the NACHT, LRR, and PYD domain-containing protein 3 (NLRP3) inflammasome plays a crucial role in regulating inflammatory diseases by overseeing the production of interleukin (IL)-1β and IL-18. Targeting its abnormal activation with drugs holds significant promise for inflammation treatment. This study highlights LCZ696, an angiotensin receptor-neprilysin inhibitor, as an effective suppressor of NLRP3 inflammasome activation in macrophages stimulated by ATP, nigericin, and monosodium urate. LCZ696 also reduces caspase-11 and GSDMD activation, lactate dehydrogenase release, propidium iodide uptake, and the extracellular release of NLRP3 and apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) in ATP-activated macrophages, suggesting a potential mitigation of pyroptosis. Mechanistically, LCZ696 lowers mitochondrial reactive oxygen species and preserves mitochondrial integrity. Importantly, it does not significantly impact NLRP3, proIL-1β, inducible nitric oxide synthase, cyclooxygenase-2 expression, or NF-κB activation in lipopolysaccharide-activated macrophages. LCZ696 partially inhibits the NLRP3 inflammasome through the induction of autophagy. In an in vivo context, LCZ696 alleviates NLRP3-associated colitis in a mouse model by reducing colonic expression of IL-1β and tumor necrosis factor-α. Collectively, these findings suggest that LCZ696 holds significant promise as a therapeutic agent for ameliorating NLRP3 inflammasome activation in various inflammatory diseases, extending beyond its established use in hypertension and heart failure treatment.

Graphical Abstract

中文翻译：

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血管紧张素 II 受体脑啡肽酶抑制剂 LCZ696 通过减少巨噬细胞线粒体功能障碍来抑制 NLRP3 炎症小体，并减轻小鼠模型中葡聚糖硫酸钠诱导的结肠炎

摘要

被称为 NACHT、LRR 和 PYD 结构域的蛋白 3 (NLRP3) 炎症小体的细胞内传感器蛋白复合物通过监督白细胞介素 (IL)-1β 和 IL-18 的产生，在调节炎症疾病中发挥着至关重要的作用。用药物靶向其异常激活为炎症治疗带来了重大希望。这项研究强调了 LCZ696（一种血管紧张素受体脑啡肽酶抑制剂）作为 ATP、尼日利亚霉素和尿酸钠刺激的巨噬细胞中 NLRP3 炎症小体激活的有效抑制剂。 LCZ696 还可以减少 ATP 激活的巨噬细胞中 caspase-11 和 GSDMD 的激活、乳酸脱氢酶的释放、碘化丙啶的摄取以及 NLRP3 和含有 caspase 募集结构域 (ASC) 的凋亡相关斑点样蛋白的细胞外释放，这表明可能具有缓解作用焦亡。从机制上讲，LCZ696 降低线粒体活性氧并保持线粒体完整性。重要的是，它不会显着影响脂多糖激活巨噬细胞中的 NLRP3、proIL-1β、诱导型一氧化氮合酶、环氧合酶-2 表达或 NF-κB 激活。 LCZ696 通过诱导自噬部分抑制 NLRP3 炎性体。在体内环境中，LCZ696 通过减少 IL-1β 和肿瘤坏死因子-α 的结肠表达来减轻小鼠模型中 NLRP3 相关的结肠炎。总的来说，这些发现表明 LCZ696 作为改善各种炎症性疾病中 NLRP3 炎症小体激活的治疗剂具有重大前景，超出了其在高血压和心力衰竭治疗中的既定用途。

图形概要