Tanshinone ⅡA prevents LPS-induced inflammatory responses in mice via inactivation of succinate dehydrogenase in macrophages

• 作者: Qiu-yan Liu Yu Zhuang Xian-rui Song Qun Niu Qiu-shuang Sun Xiao-nan Li Ning Li Bao-lin Liu Fang Huang Zhi-xia Qiu
• 来源期刊: 中国药理学报（英文版）
• 年，卷（期）: 2021,（6）
• 所属期刊栏目: Inflammation and Immunopharmacology
• 页码范围: 987-997
• 页数: 11页
• 语种: 英文

摘要

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.