Atherothrombosis and the NLRP3 inflammasome - endogenous mechanisms of inhibition.

Recently, the CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) showed the successful anti-inflammatory benefit of canakinumab, a monoclonal antibody targeting interleukin-1ß (IL-1ß) toward major cardiovascular events (MACE) in patients with a previous myocardial infarction (MI). The magnitude of reduction in MACE was directly attributed to a reduction witnessed in IL-6 and C-reactive protein (CRP) and highlighted the therapeutic potential of selectively targeting IL-1ß for atherosclerotic disease, a notion previously introduced in animal models. IL-1ß is involved in the downstream activation of the IL-6 receptor, which itself has been previously implicated as a target for atherothrombosis from Mendelian randomization studies. Further support has been garnered with the results of CIRT (Cardiovascular Inflammation Reduction Trial), which showed the inability of low-dose methotrexate to reduce IL-1ß, IL-6, or high-sensitivity CRP (hsCRP) in addition to MACE among patients with prior MI or multivessel coronary artery disease (CAD) but with normal hsCRP levels. Therefore, elucidation of therapeutic targets against the IL-1ß pathway is of immense interest currently in treating atherothrombosis. Upstream and serving as an activator of IL-1ß lies the nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome that has been well described in animal models to be activated by cholesterol crystals or hypoxia to promote cleavage and secretion of IL-1ß and IL-18 that lead to atherosclerotic deposition in arteries. Given the direct implication of an atherogenic role to the NLRP3 inflammasome in generating these cytokines, NLRP3 inhibitors are of interest with the consideration to move upstream from the initial success of anti-IL-1ß therapy. With further discussion of the existing knowledge on the proinflammatory relationship of the NLRP3 inflammasome with atherosclerosis, this review summarizes and critically evaluates the preclinical and interventional findings of endogenous NLRP3 inflammasome inhibition in attempts to elucidate anti-inflammatory mechanisms, and therapeutic targets against atherothrombosis. Further investigation focusing on the endogenous mechanisms of inhibition of the NLRP3 inflammasome would uncover diagnostic routes from defective means in inflammatory resolution. Specifically, pro-resolving lipid mediators, autophagy, and phosphorylation/dephosphorylation mechanisms are 3 points of worthy investigation from existing evidence.