NLRP3 Inflammasome Activation Through Heart-Brain Interaction Initiates Cardiac Inflammation and Hypertrophy During Pressure Overload
NLRP3 Inflammasome Activation Through Heart-Brain Interaction Initiates Cardiac Inflammation and Hypertrophy During Pressure Overload
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DOI：
10.1161/circulationaha.122.060860
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发表时间：
2023-01-24
期刊：
影响因子：
37.8
通讯作者：
Sata, Masataka
中科院分区：
文献类型：
--
作者：
Higashikuni, Yasutomi;Liu, Wenhao;Sata, Masataka
背景：心脏的机械应力，如高血压，引发炎症并导致肥厚性心脏病。然而，炎症的调节机制及其在应激心脏中的作用尚不清楚。IL-1 β（白细胞介素-1 β）是一种促炎细胞因子，可导致心脏肥厚和心力衰竭。在这里，我们发现神经信号激活NLRP3（核苷酸结合结构域，富含亮氨酸的家族，含pyrin结构域3）炎性体产生IL-1 β，诱导应激心脏的适应性肥大。方法：采用C57BL/6小鼠，NLRP3和P2RX7 （P2X嘌呤受体7）敲除小鼠，SLC17A9（一种负责ATP储存和释放的分泌囊泡蛋白）的肾上腺素能神经元特异性敲除小鼠进行分析。主动脉横缩引起压力过载。采用多种动物模型，包括用apyrase、脂多糖、2(3)- o -（4-苯甲酰苯甲酰）- atp、MCC950、抗il -1 β抗体、clonidine、pseudo麻黄碱、异丙肾上腺素和比索洛尔进行药物治疗、左星状神经节切除术和辣椒素消融心脏传入神经。观察心功能形态、基因表达、心肌IL-1 β和caspase-1活性、细胞外ATP水平。体外实验采用新生大鼠心肌细胞、成纤维细胞和人微血管内皮细胞系进行。观察细胞表面积和增殖情况。结果：NLRP3的遗传破坏导致压力过载时IL-1 β产生的显著丧失，心脏肥厚和收缩功能。骨髓移植实验揭示了心肌非免疫细胞NLRP3在心肌IL-1 β产生和心肌表型中的重要作用。细胞外ATP的药理学耗竭或P2X7受体的遗传破坏抑制了压力过载时心肌NLRP3炎性体的活性，表明ATP/P2X7轴在心脏炎症和肥厚中的重要作用。细胞外ATP在体外以NLRP3和IL-1 β依赖的方式诱导心肌细胞肥厚变化。对交感神经系统的操作表明交感传出神经是细胞外ATP的主要来源。交感传出神经ATP释放减少、心脏传入神经消融或亲脂性β受体阻滞剂降低心脏细胞外ATP水平，抑制NLRP3炎性体激活、IL-1 β生成和压力过载时适应性心脏肥厚。结论：心脏炎症和肥厚受心脑相互作用的调控。控制神经信号可能对高血压性心脏病的治疗很重要。
Background: Mechanical stress on the heart, such as high blood pressure, initiates inflammation and causes hypertrophic heart disease. However, the regulatory mechanism of inflammation and its role in the stressed heart remain unclear. IL-1 beta (interleukin-1 beta) is a proinflammatory cytokine that causes cardiac hypertrophy and heart failure. Here, we show that neural signals activate the NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing 3) inflammasome for IL-1 beta production to induce adaptive hypertrophy in the stressed heart.Methods: C57BL/6 mice, knockout mouse strains for NLRP3 and P2RX7 (P2X purinoceptor 7), and adrenergic neuron-specific knockout mice for SLC17A9, a secretory vesicle protein responsible for the storage and release of ATP, were used for analysis. Pressure overload was induced by transverse aortic constriction. Various animal models were used, including pharmacological treatment with apyrase, lipopolysaccharide, 2(3)-O-(4-benzoylbenzoyl)-ATP, MCC950, anti-IL-1 beta antibodies, clonidine, pseudoephedrine, isoproterenol, and bisoprolol, left stellate ganglionectomy, and ablation of cardiac afferent nerves with capsaicin. Cardiac function and morphology, gene expression, myocardial IL-1 beta and caspase-1 activity, and extracellular ATP level were assessed. In vitro experiments were performed using primary cardiomyocytes and fibroblasts from rat neonates and human microvascular endothelial cell line. Cell surface area and proliferation were assessed.Results: Genetic disruption of NLRP3 resulted in significant loss of IL-1 beta production, cardiac hypertrophy, and contractile function during pressure overload. A bone marrow transplantation experiment revealed an essential role of NLRP3 in cardiac nonimmune cells in myocardial IL-1 beta production and cardiac phenotype. Pharmacological depletion of extracellular ATP or genetic disruption of the P2X7 receptor suppressed myocardial NLRP3 inflammasome activity during pressure overload, indicating an important role of ATP/P2X7 axis in cardiac inflammation and hypertrophy. Extracellular ATP induced hypertrophic changes of cardiac cells in an NLRP3- and IL-1 beta-dependent manner in vitro. Manipulation of the sympathetic nervous system suggested sympathetic efferent nerves as the main source of extracellular ATP. Depletion of ATP release from sympathetic efferent nerves, ablation of cardiac afferent nerves, or a lipophilic beta-blocker reduced cardiac extracellular ATP level, and inhibited NLRP3 inflammasome activation, IL-1 beta production, and adaptive cardiac hypertrophy during pressure overload.Conclusions: Cardiac inflammation and hypertrophy are regulated by heart-brain interaction. Controlling neural signals might be important for the treatment of hypertensive heart disease.