Jiangsu Provincial Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China.
School of Basic Medical Sciences, Kunming Medical University, Kunming, China.
Elife. 2022 Feb 23;11:e72849. doi: 10.7554/eLife.72849.
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 (CATH) from tree frog () did not't show any direct anti-bacterial activity in vitro. Intriguingly, intraperitoneal injection of CATH before bacterial inoculation significantly reduced the bacterial load in tree frogs and mice, and reduced the inflammatory response induced by bacterial inoculation in mice. CATH 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 CATH significantly drove the leukocyte influx in both frogs and mice. In mice, CATH 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 CATH. CATH did not directly act as chemoattractant for phagocytes, but CATH obviously drove phagocyte migration when it was cultured with macrophages. CATH significantly elicited chemokine/cytokine production in macrophages through activating p38/ERK mitogen-activated protein kinases (MAPKs) and NF-κB p65. CATH markedly enhanced neutrophil phagocytosis via promoting the release of neutrophil extracellular traps (NETs). Additionally, CATH showed low side effects both in vitro and in vivo. Collectively, CATH 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 CATH to prevent bacterial infection.
杀菌 cathelicidins 对抗细菌感染的作用已被广泛研究。然而，非杀菌 cathelicidins 的抗菌特性和作用机制却鲜为人知。在此，我们从树蛙中发现了一种新型天然 cathelicidin（CATH），其在体外没有直接的抗细菌活性。有趣的是，在细菌接种前腹腔内注射 CATH 可显著降低树蛙和小鼠的细菌负荷，并减轻细菌接种引起的小鼠炎症反应。CATH 预处理还可提高由致死剂量细菌接种或盲肠结扎和穿刺（CLP）引起的败血症小鼠的存活率。腹腔内注射 CATH 可显著驱动青蛙和小鼠的白细胞流入。在小鼠中，CATH 可迅速驱动中性粒细胞、单核细胞/巨噬细胞流入小鼠腹腔和外周血，对 T 和 B 淋巴细胞的影响可以忽略不计，而中性粒细胞、单核细胞/巨噬细胞，但不是 T 和 B 淋巴细胞，是 CATH 预防功效所必需的。CATH 本身并不是吞噬细胞的趋化因子，但当它与巨噬细胞共培养时，CATH 明显驱动吞噬细胞迁移。CATH 通过激活 p38/ERK 丝裂原激活蛋白激酶（MAPKs）和 NF-κB p65 显著诱导巨噬细胞中细胞因子/趋化因子的产生。CATH 通过促进中性粒细胞释放细胞外陷阱（NETs）显著增强中性粒细胞吞噬作用。此外，CATH 在体外和体内均显示出低副作用。总之，CATH 作为一种宿主免疫防御调节剂，在没有直接抗菌作用的情况下提供预防细菌感染的功效。我们的研究结果揭示了一种具有独特抗菌作用的非杀菌 cathelicidin，并强调了 CATH 预防细菌感染的潜力。
