Tree Frog-Derived Cathelicidin Protects Mice against Bacterial Infection through Its Antimicrobial and Anti-Inflammatory Activities and Regulatory Effect on Phagocytes
Tree Frog-Derived Cathelicidin Protects Mice against Bacterial Infection through Its Antimicrobial and Anti-Inflammatory Activities and Regulatory Effect on Phagocytes
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DOI：
10.1021/acsinfecdis.3c00316
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发表时间：
2023-10-19
影响因子：
5.3
通讯作者：
Yang，Hailong
中科院分区：
文献类型：
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作者：
He，Yanmei;Shen，Yan;Yang，Hailong
由于在食品工业、农业和医学中的过度使用或滥用，许多病原体正在对传统抗生素产生耐药性。抗菌肽（AMP）有望成为治疗细菌感染的有效治疗选择。本文从中国林蛙Zhangixalus smaragdinus中鉴定了一种新的抗菌肽（Zs-CATH）。Zs-CATH在拟膜环境中主要采用两亲性β折叠结构。体外对革兰氏阳性菌和革兰氏阴性菌均表现出广谱抗菌活性，体内对革兰氏阴性菌大肠杆菌ATCC 25922和革兰氏阳性菌金黄色葡萄球菌ATCC 25923诱导的小鼠致死性感染有明显的保护作用。此外，Zs-CATH通过中和脂多糖（LPS）和脂磷壁酸（LTA）并促进巨噬细胞M2极化，从而抑制促炎细胞因子（TNF-α、IL-6和IL-1β）的分泌并增加M2巨噬细胞标志物IL-10、IL-4和CD 206的产生，从而发挥强大的抗炎作用。MAPK、NF-κB B等炎症信号通路及转录激活因子6（STAT 6）参与了这一作用。在小鼠中，Zs-CATH迅速将中性粒细胞和单核细胞/巨噬细胞募集到腹腔，但不募集T和B淋巴细胞。Zs-CATH没有表现出对吞噬细胞的直接趋化作用，但在巨噬细胞存在下显著促进吞噬细胞迁移。Zs-CATH刺激巨噬细胞分泌趋化因子CXCL 1、CXCL 2和CCL 2，其介导吞噬细胞的募集。此外，Zs-CATH促进活性氧（ROS）和中性粒细胞胞外陷阱（NET）的产生，这分别是中性粒细胞杀微生物活性的氧依赖性和氧非依赖性机制。Zs-CATH对哺乳动物细胞和小鼠无毒副作用。这些发现表明，除了直接抗菌活性外，Zs-CATH还具有在细菌感染期间调节免疫和炎症过程的能力，显示出作为抗感染和/或抗炎剂的开发潜力。
Due to excessive use or abuse in the food industry, agriculture, and medicine, many pathogens are developing resistance against conventional antibiotics. Antimicrobial peptides (AMPs) hold promise as effective therapeutic options for the treatment of bacterial infections. Herein, a novel cathelicidin antimicrobial peptide (Zs-CATH) was identified from the tree frogZhangixalus smaragdinus. Zs-CATH mainly adopted an amphipathic β-sheet structure in a membrane-mimetic environment. It showed broad-spectrum antibacterial activity against Gram-positive and Gram-negative bacteriain vitroand significantly protected mice from lethal infections induced by Gram-negative bacteriaEscherichia coliATCC 25922 or Gram-positive bacteriaStaphylococcus aureusATCC 25923in vivo. In addition, Zs-CATH exerted a strong anti-inflammatory effect by neutralizing lipopolysaccharide (LPS) and lipoteichoic acid (LTA) and promoting macrophage M2 polarization, thus inhibiting the secretion of proinflammatory cytokines (TNF-α, IL-6, and IL-1β) and enhancing the production of M2 macrophage markers IL-10, IL-4, and CD206. The MAPK and NF-κB inflammatory signaling pathways and transcriptional activator 6 (STAT6) were involved in this effect. In mice, Zs-CATH rapidly recruited neutrophils and monocytes/macrophages to the abdominal cavity but not T and B lymphocytes. Zs-CATH did not exhibit a direct chemoattractant effect on phagocytes but significantly promoted phagocyte migration in the presence of macrophages. Zs-CATH stimulated macrophages to secrete chemokines CXCL1, CXCL2, and CCL2, which mediated the recruitment of phagocytes. Furthermore, Zs-CATH promoted the production of reactive oxygen species (ROS) and neutrophil extracellular traps (NETs), which are oxygen-dependent and oxygen-independent mechanisms of the microbicidal activity of neutrophils, respectively. Zs-CATH exhibited no toxic side effects on mammalian cells and mice. These findings show that in addition to direct antibacterial activity, Zs-CATH also possesses the ability to modulate immune and inflammatory processes during bacterial infection, showing potential for development as anti-infective and/or anti-inflammatory agents.