College of Animal Science, Zhejiang University, Key Laboratory of Animal Nutrition & Feed Sciences, Ministry of Agriculture, Zhejiang Provincial Laboratory of Feed and Animal Nutrition, No. 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, PR China.
College of Animal Science, Zhejiang University, Key Laboratory of Animal Nutrition & Feed Sciences, Ministry of Agriculture, Zhejiang Provincial Laboratory of Feed and Animal Nutrition, No. 866 Yuhangtang Road, Hangzhou, Zhejiang 310058, PR China.
Free Radic Biol Med. 2018 Dec;129:338-353. doi: 10.1016/j.freeradbiomed.2018.09.045. Epub 2018 Sep 28.
Dysregulated activation of inflammation is associated with the development and progression of many diseases. Generation of reactive oxygen species (ROS) has been shown to promote an inflammatory response. Cathelicidin peptides not only defend against the invasion of various microbes but also play an important role in regulating immune responses. The objective of this study was to investigate the effects and mechanisms of Cathelicidin-WA (CWA) on the inflammatory response and oxidative stress in macrophages. Our results showed that CWA efficiently attenuated lipopolysaccharide (LPS)-stimulated inflammation and oxidative stress both in vivo and in vitro. Mechanistically, we found that CWA significantly reduced the LPS-induced nuclear translocation of NF-κB, thus decreasing the production of the pro-inflammatory cytokines TNF-α and IL-6 in macrophages. On the other hand, CWA markedly promoted the nuclear translocation of Nrf2 via the AKT pathway and p38 signaling. This resulted in increased expression of the anti-oxidative genes NQO-1 and HO-1 and alleviated oxidative stress in LPS-stimulated macrophages. Interestingly, the effects of CWA were diminished when AMPK was knocked down. Consistently, we noticed that CWA failed to ameliorate the LPS-induced inflammatory response and oxidative stress in AMPK knockout mice. Furthermore, we discovered that LKB1 was essential for AMPK activation by CWA. These data demonstrated for the first time that CWA attenuated LPS-stimulated inflammation and redox imbalance through regulating LKB1-AMPK signaling. Such knowledge provides new insights into the mechanisms through which Cathelicidin peptides modulate immune responses.
炎症的失调激活与许多疾病的发展和进展有关。已经表明，活性氧 (ROS) 的产生促进了炎症反应。抗菌肽不仅可以抵御各种微生物的入侵，而且在调节免疫反应方面也起着重要作用。本研究的目的是研究 Cathelicidin-WA (CWA) 对巨噬细胞炎症反应和氧化应激的影响和机制。我们的结果表明，CWA 有效地减弱了体内和体外脂多糖 (LPS) 刺激的炎症和氧化应激。从机制上讲，我们发现 CWA 显著减少了 LPS 诱导的 NF-κB 核易位，从而减少了巨噬细胞中促炎细胞因子 TNF-α和 IL-6 的产生。另一方面，CWA 通过 AKT 途径和 p38 信号显著促进 Nrf2 的核易位。这导致抗氧化基因 NQO-1 和 HO-1 的表达增加，并减轻了 LPS 刺激的巨噬细胞中的氧化应激。有趣的是，当 AMPK 被敲低时，CWA 的作用会减弱。一致地，我们注意到 CWA 未能改善 AMPK 敲除小鼠中 LPS 诱导的炎症反应和氧化应激。此外，我们发现 LKB1 对于 CWA 激活 AMPK 是必需的。这些数据首次表明，CWA 通过调节 LKB1-AMPK 信号减弱 LPS 刺激的炎症和氧化失衡。这些知识为抗菌肽调节免疫反应的机制提供了新的见解。
