RESUMO
Macrophages, which have various phenotypes and diverse functions, are becoming the target cells in inflammatory diseases. In this study, we evaluated the effects of the natural product smiglaside A, a phenylpropanoid glycoside isolated from the traditional Chinese medicinal herb Smilax riparia, on macrophage polarization and investigated the underlying mechanisms. We found that smiglaside A promoted M2 polarization and reduced M1 polarization in LPS-stimulated RAW264.7 cells and primary mouse peritoneal macrophages. Further mechanistic studies showed that the promoting effect of smiglaside A on M2 polarization was attenuated by pharmacological inhibition or gene silencing of AMP-activated protein kinase (AMPK) or peroxisome proliferator-activated receptor γ (PPARγ). Moreover, smiglaside A-enhanced PPARγ activity was prevented by the AMPK inhibitor compound C and by an siRNA. These findings indicate that the AMPK-PPARγ pathway is involved in promotion of M2 macrophages by smiglaside A. In a mouse model of LPS-induced acute lung injury, smiglaside A significantly increased the survival rate of LPS-injected mice and ameliorated the LPS-induced inflammatory response and lung damage. In addition, smiglaside A enhanced the protein expression levels of phosphorylated AMPK and PPARγ in the lung and promoted alveolar macrophages to the M2 phenotype in this mouse model. Taken together, our results indicate that smiglaside A can promote macrophage polarization to an anti-inflammatory M2 phenotype via stimulating the AMPK-PPARγ signaling pathway. Our study may provide novel approaches and/or targets for drug development to treat inflammatory diseases such as acute lung injury and sepsis.