抗菌肽通过激活 TLR4 信号通路和 P2XR/NLRP3 炎性小体加重心肌缺血/再灌注损伤。
Cathelicidin aggravates myocardial ischemia/reperfusion injury via activating TLR4 signaling and P2XR/NLRP3 inflammasome.
机构信息
Department of Metabolism and Endocrinology, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, Metabolic Syndrome Research Center, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
Department of Metabolism and Endocrinology, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China; National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology, Ministry of Education, Metabolic Syndrome Research Center, the Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
出版信息
J Mol Cell Cardiol. 2020 Feb;139:75-86. doi: 10.1016/j.yjmcc.2019.12.011. Epub 2020 Jan 23.
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 P2XR/NLRP3 inflammasome-dependent mechanism, since I/R-induced myocardial infarction was reserved by inhibition of TLR4, P2XR, 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 P2XR/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 P2XR/NLRP3 inflammasome in heart-infiltrating neutrophils, which leads to the excessive secretion of IL-1β and subsequent inflammatory injury.
目的
抗菌肽 cathelicidin（Camp）具有多功能免疫调节活性。然而，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。
方法和结果
在这项研究中，成年雄性 C57BL/6 野生型（WT）小鼠通过左前降支冠状动脉结扎进行 MI/R 损伤，缺血 45 分钟，再灌注 3 或 24 小时。在缺血和再灌注期间观察到心脏中 cathelicidin 的大量表达，主要来源于心脏浸润的中性粒细胞。在小鼠中敲除 Camp 可减少 MI/R 诱导的心肌炎症、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 CRAMP（鼠 cathelicidin 的成熟形式）会对再灌注心脏产生不利影响。CRAMP 通过 TLR4 和 P2XR/NLRP3 炎性小体依赖性机制加重 MI/R 损伤，因为在 CRAMP 处理的 WT 小鼠中抑制 TLR4、P2XR 或 NLRP3 炎性小体可保留 I/R 诱导的心肌梗死。在 MI/R 前耗尽中性粒细胞可消除 CRAMP 处理的 WT 小鼠中梗死面积的放大。在 MI/R 的早期阶段，发现心脏浸润的中性粒细胞是心肌中 IL-1β（一种“一线”促炎细胞因子）的主要细胞来源之一。在这个阶段，在 MI/R 前给予 CRAMP 仅诱导心脏浸润的中性粒细胞中 pro-IL-1β 蛋白的表达，而不是非中性粒细胞。体外实验表明，LL-37（人 cathelicidin 的成熟形式）通过刺激 TLR4 信号和 P2XR/NLRP3 炎性小体促进人中性粒细胞中 IL-1β 的加工和分泌。
结论
我们的研究结果表明，在 MI/R 的早期阶段，中性粒细胞衍生的 cathelicidin 在心脏中发挥损伤作用。Cathelicidin 通过过度激活 TLR4 信号和 P2XR/NLRP3 炎性小体在心脏浸润的中性粒细胞中加重 MI/R 损伤，导致 IL-1β 的过度分泌和随后的炎症损伤。
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