NLRP3 Inflammasome Activation Through Heart-Brain Interaction Initiates Cardiac Inflammation and Hypertrophy During Pressure Overload

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. Interleukin (IL)-1β is a proinflammatory cytokine that causes cardiac hypertrophy and heart failure. Here we show that neural signals activate the NLRP3 inflammasome for IL-1β production to induce adaptive hypertrophy in the stressed heart.
METHODS: C57BL/6 mice, knockout mouse strains for NLRP3 and P2RX7, and adrenergic neuron-specific knockout mice for SLC17A9, a secretory vesicle protein responsible for the storage and release of adenosine triphosphate (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-1β 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-1β 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-1β production, cardiac hypertrophy, and contractile function during pressure overload. A bone marrow transplantation experiment revealed an essential role of NLRP3 in cardiac non-immune cells in myocardial IL-1β 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-1β-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 β-blocker reduced cardiac extracellular ATP level, and inhibited NLRP3 inflammasome activation, IL-1β 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.