A non-bactericidal cathelicidin provides prophylactic efficacy against bacterial infection by driving phagocyte influx.
A non-bactericidal cathelicidin provides prophylactic efficacy against bacterial infection by driving phagocyte influx.
复制标题
非杀菌性导管素通过驱动吞噬细胞流入提供针对细菌感染的预防功效
作者：
Yang Y;Wu J;Li Q;Wang J;Mu L;Hui L;Li M;Xu W;Yang H;Wei L
抗菌抗菌素对细菌感染的作用已被广泛研究。然而，非抗菌抗菌肽的抗菌性能和作用机制尚不清楚。从树蛙（Polypedates puerensis）中提取的一种新型天然抗菌素（PopuCATH）在体外没有显示出任何直接的抗菌活性。有趣的是，细菌接种前腹腔注射PopuCATH可显著降低树蛙和小鼠的细菌负荷，并减轻小鼠因细菌接种引起的炎症反应。PopuCATH预处理还提高了致死剂量细菌接种或盲肠结扎穿刺（CLP）诱导的脓毒症小鼠的存活率。腹腔注射PopuCATH可显著促进青蛙和小鼠的白细胞内流。在小鼠实验中，PopuCATH可快速驱动小鼠腹腔和外周血中中性粒细胞、单核细胞/巨噬细胞内流，而对T淋巴细胞和B淋巴细胞的影响可忽略不计，并且PopuCATH的预防效果不需要中性粒细胞、单核细胞/巨噬细胞，而不需要T淋巴细胞和B淋巴细胞。PopuCATH不直接作为吞噬细胞的趋化剂，但与巨噬细胞一起培养时，PopuCATH明显推动吞噬细胞迁移。PopuCATH通过激活p38/ERK丝裂原活化蛋白激酶（MAPKs）和NF-κB p65显著诱导巨噬细胞趋化因子/细胞因子的产生。PopuCATH通过促进中性粒细胞胞外陷阱（NETs）的释放显著增强中性粒细胞吞噬。此外，PopuCATH在体外和体内的副作用都很低。总的来说，PopuCATH作为一种基于宿主的免疫防御调节剂，对细菌感染提供预防作用，但没有直接的抗菌作用。我们的研究结果揭示了一种具有独特抗菌作用的非杀菌抗菌肽，并强调了PopuCATH预防细菌感染的潜力。
The roles of bactericidal cathelicidins against bacterial infection have been extensively studied. However, the antibacterial property and mechanism of action of non-bactericidal cathelicidins are rarely known. Herein, a novel naturally occurring cathelicidin (PopuCATH) from tree frog (Polypedates puerensis) did not show any direct anti-bacterial activity in vitro. Intriguingly, intraperitoneal injection of PopuCATH before bacterial inoculation significantly reduced the bacterial load in tree frogs and mice, and reduced the inflammatory response induced by bacterial inoculation in mice. PopuCATH pretreatment also increased the survival rates of septic mice induced by a lethal dose of bacterial inoculation or cecal ligation and puncture (CLP). Intraperitoneal injection of PopuCATH significantly drove the leukocyte influx in both frogs and mice. In mice, PopuCATH rapidly drove neutrophil, monocyte/macrophage influx in mouse abdominal cavity and peripheral blood with a negligible impact on T and B lymphocytes, and neutrophils, monocytes/macrophages, but not T and B lymphocytes, were required for the preventive efficacy of PopuCATH. PopuCATH did not directly act as chemoattractant for phagocytes, but PopuCATH obviously drove phagocyte migration when it was cultured with macrophages. PopuCATH significantly elicited chemokine/cytokine production in macrophages through activating p38/ERK mitogen-activated protein kinases (MAPKs) and NF-κB p65. PopuCATH markedly enhanced neutrophil phagocytosis via promoting the release of neutrophil extracellular traps (NETs). Additionally, PopuCATH showed low side effects both in vitro and in vivo. Collectively, PopuCATH acts as a host-based immune defense regulator that provides prophylactic efficacy against bacterial infection without direct antimicrobial effects. Our findings reveal a non-bactericidal cathelicidin which possesses unique anti-bacterial action, and highlight the potential of PopuCATH to prevent bacterial infection.