【摘 要】
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Metabolic reprogramming is associated with NLRP3 inflammasome activation in activated macrophages,contributing to inflammatory responses.Tanshinone ⅡA(Tan-ⅡA)is a major constituent from Salvia miltiorrhiza Bunge,which exhibits anti-inflammatory activity.I
【机 构】
：
School of Traditional Chinese Pharmacy,China Pharmaceutical University,Nanjing 211198,China;Departme
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Metabolic reprogramming is associated with NLRP3 inflammasome activation in activated macrophages,contributing to inflammatory responses.Tanshinone ⅡA(Tan-ⅡA)is a major constituent from Salvia miltiorrhiza Bunge,which exhibits anti-inflammatory activity.In this study,we investigated the effects of Tan-ⅡA on inflammation in macrophages in focus on its regulation of metabolism and redox state.In lipopolysaccharides(LPS)-stimulated mouse bone marrow-derived macrophages(BMDMs),Tan-ⅡA(10 μM)significantly decreased succinate-boosted IL-1β and IL-6 production,accompanied by upregulation of IL-1RA and IL-10 release via inhibiting succinate dehydrogenase(SDH).Tan-ⅡA concentration dependently inhibited SDH activity with an estimated IC50 of 4.47 μM in LPS-activated BMDMs.Tan-ⅡA decreased succinate accumulation,suppressed mitochondrial reactive oxygen species production,thus preventing hypoxia-inducible factor-1 α(HIF-1α)induction.Consequently,Tan-ⅡA reduced glycolysis and protected the activity of Sirtuin2(Sirt2),an NAD+-dependent protein deacetylase,by raising the ratio of NAD+/NADH in activated macrophages.The acetylation of α-tubulin was required for the assembly of NLRP3 inflammasome;Tan-ⅡA increased the binding of Sirt2 to α-tubulin,and thus reduced the acetylation of α-tubulin,thus impairing this process.Sirt2 knockdown or application of Sirt2 inhibitor AGK-2(10 μM)neutralized the effects of Tan-ⅡA,suggesting that Tan-ⅡA inactivated NLRP3 inflammasome in a manner dependent on Sirt2 regulation.The anti-inflammatory effects of Tan-ⅡA were observed in mice subjected to LPS challenge:pre-administration of Tan-ⅡA(20 mg/kg,ip)significantly attenuated LPS-induced acute inflammatory responses,characterized by elevated IL-1β but reduced IL-10 levels in serum.The peritoneal macrophages isolated from the mice displayed similar metabolic regulation.In conclusion,Tan-ⅡA reduces HIF-1α induction via SDH inactivation,and preserves Sirt2 activity via downregulation of glycolysis,contributing to suppression of NLRP3 inflammasome activation.This study provides a new insight into the anti-inflammatory action of Tan-ⅡA from the respect of metabolic and redox regulation.
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