Anti-inflammation of torachrysone-8-O-β-ᴅ-glucoside by hurdling over morphological changes of macrophages

Abstract

Macrophages exhibit significant phenotypic plasticity to switch their functional phenotypes during inflammation and recovery. Pro-inflammatory (M1) macrophages transform their morphology from round in M0 phenotype to flat and rapidly adhere to lesion sites to recognize series of molecular patterns: damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs). Macrophages could also reprogram their metabolism to influence their function.Torachrysone-8-O-β-ᴅ-glucoside (TG), a naphthalene glucoside from Polygonum multiflorum Thunb., exhibited remarkable anti-inflammatory effect. In this study, TG significantly inhibited the Tyr-phosphorylation of focal adhesion kinase (FAK), a key regulator of morphological transformation, and downregulated FAK-mediated transcription of cytoskeleton genes. Thus, TG greatly restrained LPS-induced morphological transformation of macrophage cells into M1 type and reduced their adhesion. The inhibition of TG on FAK phosphorylation also blocked the binding between phosphor-FAK and pyruvate kinase (PK), which contributed to the inhibition of PK activity and limited the high glycolysis rate of M1 metabolic phenotype.Moreover, TG ameliorated defective function of the TCA cycle by markedly increasing of succinate dehydrogenase activity and upregulating the transcription of three rate-limiting enzymes of TCA cycle in M1-polarized macrophage cells. TG enhanced the expression of M2 polarization makers, blunting the sensitivity of RAW 264.7 cells to DAMPs/PAMPs, and inhibited nuclear translocation of NF-κB p65, thus decreased the M1-associated the release of inflammatory factors. These results demonstrated that TG could be a potent anti-inflammatory agent that curbed both the morphological and metabolic phenotype changes of macrophages and warranted further investigations on anti-inflammation effects from angles of morphology, which were unfortunately mostly neglected.