Cardiovascular Pharmacology of the NLRP3 Inflammasome

The main role of the immune response is to serve as a guardian against infections. Humans have developed a highly sophisticated system that allows for a rapid response to microbial infections and to repair injury secondary to invasive infections. This very active immune response has undoubtedly protected mankind against pestilences over the millennia. It is now understood that an overactive immune response without microbial infection—also called sterile inflammation—is at the basis of the pathophysiology of many acute and chronic illnesses.

In the next issue of the Journal of Cardiovascular Pharmacology (September–October), we have asked international experts to explain how the NLRP3 inflammasome is a central mechanism in the response to injury in acute myocardial infarction and other acute cardiovascular illnesses and how a persistently active NLRP3 inflammasome may contribute to chronic degenerative illnesses.

Dr Toldo et al describe how the inflammasome functions as macromolecular machinery for injury sensing and amplification of the inflammatory response.¹ The inflammasome is composed of sensor proteins—members of the NOD-like family of proteins—adaptor proteins—mainly ASC (apoptosis speck-like protein containing a caspase-1 recruitment domain), and effectors—caspase-1, also known as interleukin-1β (IL-1β)–converting enzyme for its role in processing and activating IL-1β. NLRP3 is the inflammasome sensor most widely characterized in cardiovascular disease and has the peculiar characteristic of functioning as a sensor for not only a variety of microbial antigens but also several unrelated products of cellular injury or metabolic stress with a common mechanism of lysosomal destabilization.

The role of the inflammasome was initially described and then widely characterized in leukocytes, the prototypical inflammatory cell. The machinery for inflammasome formation is however either constitutively expressed or inducible on proinflammatory signaling culminating in activation of NF-κB in virtually every cell type. Dr. Takahashi² describes the cell-specific signaling of the NLRP3 inflammasome in myocardial infarction. Although the NLRP3 inflammasome in leukocytes is mainly a mechanism for production and release of proinflammatory cytokines such as IL-1β, in other cell types such as cardiomyocytes, activation of the inflammasome is rather disconnected from the production of IL-1β but rather culminates in inflammatory cell death (pyroptosis) and release of intracellular content. In fibroblasts, NLRP3 inflammasome activation is paired with a profibrotic phenotype change. Defining the complexity of the different roles of the NLRP3 inflammasome in different cell types may help identify targeted therapeutic strategies.

Activation of the inflammasome and of caspase-1, in particular, in the setting of acute myocardial ischemia and reperfusion has been shown to be a major contributor to the final infarct size. Dr. Davidson et al review and discuss the specific role of caspase-1 and the evidence supporting inhibition of the inflammasome and of caspase-1 as a potential therapeutic target in myocardial ischemia/reperfusion injury.³

As already mentioned, the role of the NLRP3 inflammasome extends beyond the function of guardian against microbial infections and also beyond its role in the response to tissue injury. Much has been published on the activation of the NLRP3 inflammasome by lysosome destabilization by aggregates or crystals of cholesterol or uric acid. Dr. Aukurst et al were asked to review and summarize how the NRLP3 inflammasome is activated in the context of chronic metabolic stress due to diet-induced obesity and diabetes.⁴ This is an important aspect as it links impairments in metabolism to chronic inflammation and cardiovascular dysfunction.

Although NLRP3 is mostly known for its role, the formation of the inflammasome, and amplification of the inflammatory response, the protein has other functions that may in part be separate from inflammation. Dr. Zuurbier⁵ reviews these so-called independent functions of NLRP3, which may be involved in cardioprotective signaling. A complete understanding of NLRP3 signaling is essential for the planning of targeted therapies.

NLRP3 inflammasome inhibitors have been explored in preclinical models of cardiovascular diseases as well as in other models of chronic degenerative diseases and cancer. Dr. Marchetti⁶ reviews the biochemistry and molecular aspects of the proposed inflammasome inhibitors, ranging from pre-existing drugs that have more recently been shown to target the NLRP3 inflammasome (eg, colchicine) to drugs in phase I–II clinical development specifically designed to inhibit NLRP3 (eg, OLT1177).

Clinical evidence in support of NLRP3 inflammasome inhibitors is rather limited. The rationale for inhibiting the NLRP3 inflammasome stems from the large bulk of evidence supporting IL-1β as a therapeutic target.⁷ Drs. Buckley and Libby⁸ analyze and summarize the pharmacology of currently available strategies and the effects on clinical outcomes.

In summary, the inflammatory response to sterile insult contributes to further injury and dysfunction. IL-1β and the NLRP3 inflammasome have been identified as suitable therapeutic targets. We hope the readers of the Journal of Cardiovascular Pharmacology will find this series of articles, ranging from molecular mechanisms to pharmacotherapeutic aspects, of value for understanding this novel therapeutic class.