Department of Clinical and Translational Science, Creighton University School of Medicine, Omaha, Nebraska.
Department of Clinical and Translational Science, Creighton University School of Medicine, Omaha, Nebraska; Department of Translational Research, Western University of Health Sciences, Pomona, California.
Transl Res. 2020 Jan;215:75-85. doi: 10.1016/j.trsl.2019.08.003. Epub 2019 Aug 12.
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.
最近，CANTOS（Canakinumab Anti-Inflammatory Thrombosis Outcomes Study）研究表明，靶向白细胞介素-1β（IL-1β）的单克隆抗体卡那单抗可降低先前心肌梗死（MI）患者的主要心血管事件（MACE）发生率，具有成功的抗炎作用。MACE 发生率的降低与 IL-6 和 C 反应蛋白（CRP）的降低直接相关，这突出了针对动脉粥样硬化疾病选择性靶向 IL-1β的治疗潜力，这一概念先前在动物模型中提出。IL-1β参与下游白细胞介素-6 受体的激活，该受体本身已被 Mendelian 随机化研究证实为动脉粥样血栓形成的靶点。CIRT（心血管炎症减少试验）的结果进一步提供了支持，该研究表明，在先前有 MI 或多血管 CAD 但 hsCRP 水平正常的患者中，低剂量甲氨蝶呤无法降低 IL-1β、IL-6 或高敏 CRP（hsCRP），也无法降低 MACE。因此，目前针对 IL-1β 通路的治疗靶点的阐明对于治疗动脉粥样血栓形成具有重要意义。作为 IL-1β 的上游激活剂，核苷酸结合寡聚化结构域样受体蛋白 3（NLRP3）炎性小体已在动物模型中得到很好的描述，其可被胆固醇晶体或缺氧激活，促进 IL-1β 和 IL-18 的切割和分泌，导致动脉粥样硬化沉积。鉴于 NLRP3 炎性小体在产生这些细胞因子中的致动脉粥样作用的直接意义，NLRP3 抑制剂具有一定的研究价值，因为它可以考虑从抗 IL-1β 治疗的最初成功中向前推进。本文进一步讨论了 NLRP3 炎性小体与动脉粥样硬化之间的促炎关系的现有知识，总结和批判性地评估了内源性 NLRP3 炎性小体抑制在阐明抗炎机制和动脉粥样血栓形成治疗靶点方面的临床前和干预性研究结果。进一步关注 NLRP3 炎性小体的内源性抑制机制将揭示炎症解决缺陷途径的诊断方法。具体而言，从现有证据来看，促解决脂质介质、自噬和磷酸化/去磷酸化机制是 3 个值得研究的要点。
