Abstract
Dehydrocostus lactone (DHL), a natural sesquiterpene lactone isolated from the traditional Chinese herbs Saussurea lappa and Inula helenium L., has important anti-inflammatory properties used for treating colitis, fibrosis, and Gram-negative bacteria-induced acute lung injury (ALI). However, the effects of DHL on Gram-positive bacteria-induced macrophage activation and ALI remains unclear. In this study, we found that DHL inhibited the phosphorylation of p38 MAPK, the degradation of IκBα, and the activation and nuclear translocation of NF-κB p65, but enhanced the phosphorylation of AMP-activated protein kinase (AMPK) and the expression of Nrf2 and HO-1 in lipoteichoic acid (LTA)-stimulated RAW264.7 cells and primary bone-marrow-derived macrophages (BMDMs). Given the critical role of the p38 MAPK/NF-κB and AMPK/Nrf2 signaling pathways in the balance of M1/M2 macrophage polarization and inflammation, we speculated that DHL would also have an effect on macrophage polarization. Further studies verified that DHL promoted M2 macrophage polarization and reduced M1 polarization, then resulted in a decreased inflammatory response. An in vivo study also revealed that DHL exhibited anti-inflammatory effects and ameliorated methicillin-resistant Staphylococcus aureus (MRSA)-induced ALI. In addition, DHL treatment significantly inhibited the p38 MAPK/NF-κB pathway and activated AMPK/Nrf2 signaling, leading to accelerated switching of macrophages from M1 to M2 in the MRSA-induced murine ALI model. Collectively, these data demonstrated that DHL can promote macrophage polarization to an anti-inflammatory M2 phenotype via interfering in p38 MAPK/NF-κB signaling, as well as activating the AMPK/Nrf2 pathway in vitro and in vivo. Our results suggested that DHL might be a novel candidate for treating inflammatory diseases caused by Gram-positive bacteria.
Highlights
Bacterial infection is the main cause of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), which is characterized by severe inflammation and can result in respiratory failure [1]
We found that Dehydrocostus lactone (DHL) promoted the polarization of macrophages from M1 phenotype to M2 phenotype, and this process was involved in the p38 mitogen-activated protein kinase (MAPK)/nuclear factor-κB (NF-κB) and AMPK/nuclear factor erythroid 2-releated factor 2 (Nrf2) signaling pathways
To elucidate the effects of DHL on the activation of p38 MAPK and NF-κB induced by Lipoteichoic acid (LTA) in macrophages, RAW264.7 cells (Figure 1A,C–E,I) and primary bone-marrow-derived macrophages (BMDMs) (Figure 1F–H) were used in this study
Summary
Bacterial infection is the main cause of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), which is characterized by severe inflammation and can result in respiratory failure [1]. During Gram-positive bacteria-triggered inflammatory responses, toll-like receptor 2 (TLR2) recruits myeloid differentiation factor 88 (MyD88), and activates the downstream signaling cascade, including the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and the degradation of IκBα, which result in activation and nuclear translocation of nuclear factor-κB (NF-κB) [9,10]. TLR2-mediated signaling promotes M1 phenotype macrophages, which are characterized by elevated expression of inducible nitric oxide synthase (iNOS) and increased production of proinflammatory cytokines (e.g., TNF-α, IL-1β, and IL-6) [11]. Few compounds have been authenticated as having the ability to alleviate ALI by mediating the ratio of the M1/M2 phenotype, especially in Gram-positive bacteria-induced ALI
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