Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, China.
Central Arkansas Veterans Healthcare System and Department of Internal Medicine, University of Arkansas for Medical Sciences, Little Rock, USA.
Theranostics. 2020 May 30;10(16):7100-7110. doi: 10.7150/thno.45939. eCollection 2020.
Both PCSK9 and NLRP3 inflammasome play important roles in atherogenesis. This study was designed to test the hypothesis that NLRP3 inflammasome via IL-1β induces PCSK9 secretion. The inter-twined relationship between NLRP3 inflammasome, IL-1β and PCSK9 may be relevant in atherogenesis. We studied NLRP3 inflammasome-mediated PCSK9 secretion in mouse peritoneal macrophages and in a variety of tissues, such as liver, kidney and small intestine. Macrophages were derived from wild-type (WT) and a variety of gene deletion mice to define the mechanistic basis of NLRP3 inflammasome -mediated PCSK9 secretion. Additional studies were performed in high-fat diet fed mice. We observed that NLRP3 and its downstream signals ASC, Caspase-1, IL-18, and IL-1β all participate in PCSK9 secretion. IL-1β seems to be more important than IL-18 in the induction of PCSK9 secretion. Further, there appears to be significant involvement of MAPKs in this process. Lastly, we observed that mice fed high fat diet have high expression of NLRP3 and a greater secretion of PCSK9 than mice fed a standard diet, and this increased secretion of PCSK9 in high fat diet-fed mice was attenuated in mice. Conclusions: This study based on extensive in vitro and in vivo data provides evidence that NLRP3 inflammasome via IL-1β plays an important role in determining PCSK9 secretion, particularly in the presence of high-fat diet.
PCSK9 和 NLRP3 炎性小体在动脉粥样硬化形成中都起着重要作用。本研究旨在检验以下假说，即 NLRP3 炎性小体通过 IL-1β 诱导 PCSK9 分泌。NLRP3 炎性小体、IL-1β 和 PCSK9 之间的交织关系可能与动脉粥样硬化形成有关。我们研究了 NLRP3 炎性小体介导的小鼠腹腔巨噬细胞和多种组织（如肝、肾和小肠）中的 PCSK9 分泌。巨噬细胞来自野生型（WT）和多种基因缺失小鼠，以定义 NLRP3 炎性小体介导的 PCSK9 分泌的机制基础。还在高脂肪饮食喂养的小鼠中进行了额外的研究。我们观察到 NLRP3 及其下游信号 ASC、Caspase-1、IL-18 和 IL-1β 均参与 PCSK9 分泌。IL-1β 在诱导 PCSK9 分泌中的作用似乎比 IL-18 更重要。此外，MAPKs 在这个过程中似乎有重要的参与。最后，我们观察到，喂食高脂肪饮食的小鼠比喂食标准饮食的小鼠具有更高的 NLRP3 表达和更高的 PCSK9 分泌，而高脂肪饮食喂养的小鼠中这种 PCSK9 分泌的增加在基因缺失小鼠中减弱。结论：这项基于广泛的体外和体内数据的研究提供了证据，表明 NLRP3 炎性小体通过 IL-1β 在决定 PCSK9 分泌中起着重要作用，特别是在高脂肪饮食存在的情况下。
