NLRP3-mediated inflammation in cardio-oncology: sterile yet harmful

Abstract

Despite significant advances and the continuous development of novel, effective therapies to treat a variety of malignancies, cancer therapy-induced cardiotoxicity has been identified as a prominent cause of morbidity and mortality, closely competing with secondary malignancies. This unfortunate limitation has prompted the inception of the field of cardio-oncology with its purpose to provide the necessary knowledge and key information on mechanisms that support the use of the most efficacious cancer therapy with minimal or no interruption while paying close attention to preventing cardiovascular related morbidity and mortality. Several mechanisms that contribute to cancer therapy-induced cardiotoxicity have been proposed and studied. These mainly involve mitochondrial dysfunction and reactive oxygen species-induced oxidative stress, lysosomal damage, impaired autophagy, cell senescence, DNA damage, and sterile inflammation with the formation and activation of the NLRP3 inflammasome. In this review, we focus on describing the principal mechanisms for different classes of cancer therapies that lead to cardiotoxicity involving the NLRP3 inflammasome. We also summarize current evidence of cardio-protection with inflammasome inhibitors in the context of heart disease in general, and further highlight the potential application of this evidence for clinical translation in at risk patients for the purpose of preventing cancer therapy associated cardiovascular morbidity and mortality.

Fig 1.

Proposed mechanism of the activation of NLRP3 inflammasome following the administration of cancer therapies. Cancer treatment induces cardiomyocyte injury, which mediates the priming signaling of the NLRP3 inflammasome. NF-KB is activated, migrates to the nucleus, and begins the synthesis of the inactive NLRP3 components. Mitochondrial dysfunction in the heart consequently results in oxidative stress. Coupled with impaired autophagy, this then leads to the triggering of the NLRP3. The NLRP3 then oligomerizes and induces an auto-proteolytical activation of caspase-1. Active caspase-1 processes pro-IL1β and pro-IL18 into their mature forms, and triggers pyroptotic myocardial cell death. This NLRP3-mediated cardiac injury can induce long-term consequences on the heart, leading to the onset of heart failure.