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 P2X7R/NLRP3 inflammasome-dependent mechanism, since I/R-induced myocardial infarction was reserved by inhibition of TLR4, P2X7R, 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-1β (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-1β 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-1β from human neutrophils via stimulating TLR4 signaling and P2X7R/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 P2X7R/NLRP3 inflammasome in heart-infiltrating neutrophils, which leads to the excessive secretion of IL-1β and subsequent inflammatory injury.

中文翻译：

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Cathelicidin通过激活TLR4信号传导和P2X7R / NLRP3炎性小体加重心肌缺血/再灌注损伤。

目的抗菌肽cathelicidin（Camp）具有多功能的免疫调节活性。然而，其在炎症相关的心肌缺血/再灌注（MI / R）损伤中的作用仍不清楚。方法和结果在这项研究中，成年雄性C57BL / 6野生型（WT）小鼠通过冠状动脉左前降支结扎45分钟，然后再灌注3或24小时，遭受MI / R损伤。在缺血和再灌注过程中观察到大量的cathelicidin心脏表达，其主要来源于心脏浸润性中性粒细胞。敲除小鼠中的Camp可以减少MI / R引起的心肌炎症，梗塞面积和循环cTnI水平（心脏损伤的指标）。在MI / R之前立即给野生型小鼠施用CRAMP（鼠类Cathelicidin的成熟形式）会对再灌注心脏产生不利影响。CRAMP通过TLR4和P2X7R / NLRP3炎性小体依赖性机制加重MI / R损伤，因为I / R诱导的心肌梗死是通过抑制CRAMP处理的WT小鼠中的TLR4，P2X7R或NLRP3炎性小体而保留的。MI / R前中性粒细胞的消耗消除了CRAMP处理的WT小鼠中梗死面积的扩大。在MI / R早期，发现心脏浸润性中性粒细胞是心肌IL-1β（“一线”促炎性细胞因子）的主要细胞来源之一。在这个阶段，在心梗中性粒细胞中，就在MI / R之前施用CRAMP可以诱导前IL-1β蛋白表达，而在非中性粒细胞中则不。体外实验表明，LL-37（人类cathelicidin的成熟形式）治疗可通过刺激TLR4信号传导和P2X7R / NLRP3炎性体来促进中性粒细胞IL-1β的加工和分泌。结论我们的研究结果表明，在MI / R的早期，中性粒细胞衍生的cathelicidin在心脏中起有害作用。Cathelicidin通过过度激活心脏浸润性中性粒细胞中的TLR4信号和P2X7R / NLRP3炎性小体来加重MI / R损伤，这导致IL-1β的过度分泌和随后的炎性损伤。中性粒细胞衍生的cathelicidin在心脏中起有害作用。Cathelicidin通过过度激活心脏浸润性中性粒细胞中的TLR4信号传导和P2X7R / NLRP3炎性小体来加重MI / R损伤，从而导致IL-1β的过度分泌和随后的炎性损伤。中性粒细胞衍生的cathelicidin在心脏中起有害作用。Cathelicidin通过过度激活心脏浸润性中性粒细胞中的TLR4信号和P2X7R / NLRP3炎性小体来加重MI / R损伤，这导致IL-1β的过度分泌和随后的炎性损伤。