Interleukin-1 and the Inflammasome as Therapeutic Targets in Cardiovascular Disease.
Interleukin-1 and the Inflammasome as Therapeutic Targets in Cardiovascular Disease.
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白介素-1和炎性体作为心血管疾病的治疗靶标。
DOI：
10.1161/circresaha.120.315937
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发表时间：
2020-04-24
影响因子：
20.1
通讯作者：
Dinarello CA
中科院分区：
文献类型：
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作者：
Abbate A;Toldo S;Marchetti C;Kron J;Van Tassell BW;Dinarello CA
称为NLRP 3的细胞内传感蛋白（对于含有NACHT、LRR和PYD结构域的蛋白3）形成称为NLRP 3炎性体的大分子结构。NLRP 3炎性体在炎症中起主要作用，特别是在白细胞介素-1 β（IL-1β）的产生中。IL-1β是研究最多的IL-1家族细胞因子，包括11个成员，其中IL-1α和IL-18。在此，我们总结了临床前和临床研究结果，支持NLRP 3炎性体和IL-1细胞因子在动脉粥样硬化的形成、进展和并发症中，在缺血性（急性心肌梗死，AMI）和非缺血性心肌损伤（心肌炎）以及心力衰竭（HF）进展中的关键发病作用。我们还审查了临床上可用的IL-1抑制剂，尽管目前尚未批准用于心血管适应症，并讨论了其他IL-1抑制剂，目前尚未批准，以及目前正在临床开发的口服NLRP 3炎性体抑制剂。在一项包括全球10，061名患者的大型III期临床试验中，IL-1β抗体卡那单抗可预防既往AMI患者缺血事件的复发。II期临床试验显示，阿那白滞素（重组IL-1受体拮抗剂）在ST段抬高型AMI或射血分数降低的HF患者中的数据很有希望。阿那白滞素还改善了心包炎患者的结局，现在被认为是复发性/难治性心包炎患者的二线治疗标准。瑞那西普是一种可溶性IL-1受体嵌合融合蛋白，可中和IL-1α和IL-1β，在复发性/难治性心包炎的II期研究中也显示出有希望的结果。总之，有压倒性的证据将NLRP 3炎性体和IL-1细胞因子与心血管疾病的发病机制联系起来。未来可能包括靶向抑制剂，以阻止IL-1亚型，并可能口服NLRP 3炎性体抑制剂，在广泛的心血管疾病。
The intracellular sensing protein termed NLRP3 (for NACHT, LRR, and PYD domains-containing protein 3) forms a macromolecular structure called the NLRP3 inflammasome. The NLRP3 inflammasome plays a major role in inflammation, particular in the production of interleukin-1β (IL-1β). IL-1β is the most studied of the the IL-1 family of cytokines, including 11 members among which IL-1α and IL-18. Here, we summarize pre-clinical and clinical findings supporting the key pathogenetic role of the NLRP3 inflammasome and IL-1 cytokines in the formation, progression and complications of atherosclerosis, in ischemic (acute myocardial infarction, AMI), and non-ischemic injury to the myocardium (myocarditis) and the progression to heart failure (HF). We also review the clinically available IL-1 inhibitors, although not currently approved for a cardiovascular indications, and discuss other IL-1 inhibitors, not currently approved, as well as oral NLRP3 inflammasome inhibitors currently in clinical development. Canakinumab, IL-1β antibody, prevented the recurrence of ischemic events in patients with prior AMI in a large phase III clinical trial including 10,061 patients world-wide. Phase II clinical trials show promising data with anakinra, recombinant IL-1 receptor antagonist, in patients with ST segment elevation AMI or HF with reduced ejection fraction. Anakinra also improved outcomes in patients with pericarditis and it is now considered standard of care as second line treatment for patients with recurrent/refractory pericarditis. Rilonacept, a soluble IL-1 receptor chimeric fusion protein neutralizing IL-1α and IL-1β, has also shown promising results in a phase II study in recurrent/ refractory pericarditis. In conclusion, there is overwhelming evidence linking the NLRP3 inflammasome and the IL-1 cytokines with the pathogenesis of cardiovascular diseases. The future will likely include targeted inhibitors to block the IL-1 isoforms, and possibly oral NLRP3 inflammasome inhibitors, across a wide spectrum of cardiovascular diseases.