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-1β (interleukin-1β) is a proinflammatory cytokine that causes cardiac hypertrophy and heart failure. Here, we show that NLRP3 (neural signals activate the nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing 3) inflammasome for IL-1β 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-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 nonimmune 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.

Human diseases are caused by dysregulation of cellular biological programs that are encoded in DNA. Unveiling the endogenous programs and encoding new programs into the genome are key to creating novel diagnostic and therapeutic strategies. CRISPR/Cas9, originally identified in bacteria, has revolutionized genome editing in mammalian cells. Recent advances in CRISPR technologies have provided new programmable platforms for modifying cell function and behavior. CRISPR-based transcriptional regulators and modified gRNAs have enabled multiplexed regulation and visualization of genome dynamics with spatiotemporal precision. Using these toolkits, genome-scale screening platforms can identify key genetic elements or combinations thereof that modulate phenotypes in mammalian cells. In addition, imaging platforms for multiplexed genomic labeling have been created to study the conformation and dynamics of chromatin in living cells, which are essential for genome function. Furthermore, CRISPR-based computation and memory platforms have been built in living mammalian cells by using DNA as a data processing and storage medium to regulate and monitor cellular behaviors. The conditional regulation of CRISPR-based parts has enabled the design of complex multilayered biological programs. CRISPR-based memory platforms can continuously record biological events as mutations in defined DNA loci. By making use of base editors, CRISPR-based computation and memory platforms have been interconnected to perform logic operations based on past events. These technologies open up new avenues for understanding biological phenomena and designing mammalian cells as living machines for biomedical applications.

The ability to process and store information in living cells is essential for developing next-generation therapeutics and studying biology in situ. However, existing strategies have limited recording capacity and are challenging to scale. To overcome these limitations, we developed DOMINO, a robust and scalable platform for encoding logic and memory in bacterial and eukaryotic cells. Using an efficient single-nucleotide-resolution Read-Write head for DNA manipulation, DOMINO converts the living cells' DNA into an addressable, readable, and writable medium for computation and storage. DOMINO operators enable analog and digital molecular recording for long-term monitoring of signaling dynamics and cellular events. Furthermore, multiple operators can be layered and interconnected to encode order-independent, sequential, and temporal logic, allowing recording and control over the combination, order, and timing of molecular events in cells. We envision that DOMINO will lay the foundation for building robust and sophisticated computation-and-memory gene circuits for numerous biotechnological and biomedical applications.