Cathelicidin aggravates myocardial ischemia/reperfusion injury via activating TLR4 signaling and P2X7R/NLRP3 inflammasome
Cathelicidin aggravates myocardial ischemia/reperfusion injury via activating TLR4 signaling and P2X7R/NLRP3 inflammasome
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DOI：
10.1016/j.yjmcc.2019.12.011
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发表时间：
2020-02-01
影响因子：
5
通讯作者：
Liu, Feng
中科院分区：
文献类型：
--
作者：
Wu, Yan;Zhang, Yacheng;Liu, Feng
目的：抗菌肽长春花素(CAMP)具有多功能免疫调节活性。但其在炎症相关心肌缺血/再灌注(MI/R)损伤中的作用尚不清楚。方法与结果：成年雄性C57BL/6野生型(WT)小鼠采用冠状动脉左前降支结扎45min后再灌流3或24 h造成心肌缺血/再灌注损伤。心肌缺血再灌注期大量表达长春花碱，其主要来源为心脏浸润性中性粒细胞。在小鼠中敲除cAMP可减少MI/R引起的心肌炎症、梗死面积和循环cTnI水平(心脏损伤的指标)。在MI/R前立即给予WT小鼠抽筋(成熟形式的小鼠去甲肾上腺素)对再灌流的心脏产生不利影响。痉挛通过TLR4和P2X(7)R/NLRP3炎症依赖机制加重MI/R损伤，因为在抽筋治疗的WT小鼠中，通过抑制TLR4、P2X(7)R或NLRP3炎症小体来保留I/R诱导的心肌梗死。在MI/R前去除中性粒细胞可以抑制抽筋治疗的WT小鼠的梗塞面积的扩大。在MI/R早期，心脏浸润性中性粒细胞被发现是心肌IL-1β(一种“第一线”促炎细胞因子)的主要细胞来源之一。在这一阶段，MI/R前抽筋给药可诱导心脏浸润性中性粒细胞表达前IL-1β蛋白，而非中性粒细胞则不表达。体外实验表明，IL-37可通过刺激TLR4信号转导和P2X(7)R/NLRP3炎症反应促进中性粒细胞分泌IL-1β。结论：在MI/R早期，中性粒细胞来源的长春花碱对心脏有损伤作用。长春花碱通过过度激活心脏浸润性中性粒细胞中的TLR4信号和P2X(7)R/NLRP3炎性小体，导致IL-1β的过度分泌，从而加重MI/R损伤。
Aims: The antimicrobial peptide cathelicidin (Camp) has multifunctional immunomodulatory activities. However, its roles in inflammation-related myocardial ischemia/reperfusion (MI/R) injury remain unclear.Methods and results: In this study, adult male C57BL/6 wild-type (WT) mice were subjected to MI/R injury by left anterior descending coronary artery ligation for 45 min followed by 3 or 24 h of reperfusion. An abundant cardiac expression of cathelicidin was observed during ischemia and reperfusion, which was mainly derived from heart-infiltrating neutrophils. Knockout of Camp in mice reduced MI/R-induced myocardial inflammation, infarct size, and circulating cTnI levels (an indicator of heart damage). CRAMP (the mature form of murine cathelicidin) administration of WT mice immediately before MI/R exerted detrimental effects on the reperfused heart. CRAMP exacerbates MI/R injury via a TLR4 and P2X(7)R/NLRP3 inflammasome-dependent mechanism, since I/R-induced myocardial infarction was reserved by inhibition of TLR4, P2X(7)R, or NLRP3 inflammasome in CRAMP-treated WT mice. Depletion of neutrophils before MI/R abrogated the amplification of infarct size in CRAMP-treated WT mice. Heart-infiltrating neutrophils were found to be one of major cellular sources of myocardial IL-1 beta (a "first line" pro-inflammatory cytokine) at the early stage of MI/R. At this stage, CRAMP administration just before MI/R induced pro-IL-1 beta protein expression in heart-infiltrating neutrophils, but not in non-neutrophils. In vitro experiments showed that LL-37 (the mature form of human cathelicidin) treatment promotes the processing and secretion of IL-1 beta from human neutrophils via stimulating TLR4 signaling and P2X(7)R/NLRP3 inflammasome.Conclusions: Our findings reveal that, at the early stage of MI/R, neutrophil-derived cathelicidin plays an injurious role in the heart. Cathelicidin aggravates MI/R injury by over-activating TLR4 signaling and P2X(7)R/NLRP3 inflammasome in heart-infiltrating neutrophils, which leads to the excessive secretion of IL-1 beta and subsequent inflammatory injury.