The Nlrp3 inflammasome promotes myocardial dysfunction in structural cardiomyopathy through interleukin‐1β

Abstract

New findings r What is the central question of this study?Heart failure is associated with persistent sterile inflammation that worsens disease severity; however, the molecular mechanisms behind cytokine recruitment and their relevance in the diseased myocardium remain unknown. r What is the main finding and its importance?We show that interleukin-1β is activated downstream of the Nlrp3 inflammasome in calcineurin-transgene-induced structural heart disease. Genetic deletion of Nlrp3 abrogated inflammasome signalling and interleukin-1β release, improving function. The role of Nlrp3 in non-ischaemic cardiomyopathy and the utility of inflammasome antagonism have not yet been explored, revealing potential for translational application.Heart failure is associated with a low-grade and chronic cardiac inflammation that impairs function; however, the mechanisms by which this sterile inflammation occurs in structural heart disease remain poorly defined. Cardiac-specific heterozygous overexpression of the calcineurin transgene (CNTg) in mice results in cardiac hypertrophy, inflammation, apoptosis and ventricular dilatation. We hypothesized that activation of the Nlrp3 inflammasome, an intracellular danger-sensing pathway required for processing the pro-inflammatory cytokine interleukin-1β (IL-1β), may contribute to myocardial dysfunction and disease progression. Here we report that Nlrp3 mRNA was increased in CNTg mice compared with wild-type. Consistent with inflammasome activation, CNTg animals had increased conversion of procaspase-1 to cleaved and activated forms, as well as markedly increased serum IL-1β. Blockade of IL-1β signalling via chronic IL-1 receptor antagonist therapy reduced cardiac inflammation and myocyte pathology in CNTg mice, resulting in improved systolic performance. Furthermore, genetic ablation of Nlrp3 in CNTg mice reduced pro-inflammatory cytokine maturation and cardiac inflammation, as well as improving systolic performance. These findings indicate that activation of the Nlrp3 inflammasome in CNTg mice promotes myocardial inflammation and systolic dysfunction through the production of pro-inflammatory IL-1β. Blockade of IL-1β signalling with the IL-1 receptor antagonist reverses these phenotypes and offers a possible therapeutic approach in the management of heart failure.

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“…These studies are consistent with findings of mitochondrial dysfunction and increased organellar fission in brain samples of autistic individuals [79]. Similar involvement of NLRP3-associated inflammation is found in Alzheimer's disease [80] and cardiomyopathy [81]. These associations strongly suggest that inflammation and mitochondria comprise a pathogenic axis that is likely to play a role in a wide range of prominent human diseases.…”

Lysosomes Integrate Metabolic-Inflammatory Cross-talk in Primary Macrophage Inflammasome Activation

“…Thus, calcineurin appears to be one of the important calciumregulated proteins that modulate the expression of pro-IL-1␤. Further evidence supporting the relevance of this pathway comes from a recent report demonstrating that calcineurin overexpression in cardiac myocytes also leads to enhanced IL-1␤ release with activation of the NLRP3 inflammasome (30).…”

Q705K variant in NLRP3 gene confers protection against myocardial infarction in female individuals

“…Several recent studies have also revealed the association of the Q705K polymorphism in the NLRP3 gene (rs35829419) with various inflammatory diseases including celiac disease (9), diabetes type-1 (8), abdominal aortic aneurysms (14), Crohn's disease (15) and rheumatoid arthritis (10 CARD8 (C10X) genes was found to be associated with rheumatoid arthritis (10) and Crohn's disease (15,16). Considering a possible key role of the NLRP3 inflammasome in promoting myocardial inflammation (17) and athero sclerosis through the production of pro-inflammatory cytokine IL-1β (18), the aim of the present study was to investigate the effect of Q705K polymorphism in NLRP3 gene and the risk of developing MI in a northern Swedish population.…”