PMID- 33028985 OWN - NLM STAT- MEDLINE DCOM- 20211007 LR - 20240226 IS - 1745-7254 (Electronic) IS - 1671-4083 (Print) IS - 1671-4083 (Linking) VI - 42 IP - 6 DP - 2021 Jun TI - Tanshinone IIA prevents LPS-induced inflammatory responses in mice via inactivation of succinate dehydrogenase in macrophages. PG - 987-997 LID - 10.1038/s41401-020-00535-x [doi] AB - 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 muM) significantly decreased succinate-boosted IL-1beta 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 IC(50) of 4.47 muM in LPS-activated BMDMs. Tan-IIA decreased succinate accumulation, suppressed mitochondrial reactive oxygen species production, thus preventing hypoxia-inducible factor-1alpha (HIF-1alpha) 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 alpha-tubulin was required for the assembly of NLRP3 inflammasome; Tan-IIA increased the binding of Sirt2 to alpha-tubulin, and thus reduced the acetylation of alpha-tubulin, thus impairing this process. Sirt2 knockdown or application of Sirt2 inhibitor AGK-2 (10 muM) 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-1beta but reduced IL-10 levels in serum. The peritoneal macrophages isolated from the mice displayed similar metabolic regulation. In conclusion, Tan-IIA reduces HIF-1alpha 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. FAU - Liu, Qiu-Yan AU - Liu QY AD - School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. FAU - Zhuang, Yu AU - Zhuang Y AD - School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. FAU - Song, Xian-Rui AU - Song XR AD - School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. FAU - Niu, Qun AU - Niu Q AD - School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. FAU - Sun, Qiu-Shuang AU - Sun QS AD - School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. FAU - Li, Xiao-Nan AU - Li XN AD - Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, State University of New York at Buffalo, Buffalo, NY, USA. FAU - Li, Ning AU - Li N AD - National Experimental Teaching Demonstration Center of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. FAU - Liu, Bao-Lin AU - Liu BL AD - School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. FAU - Huang, Fang AU - Huang F AD - School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. chengtianle007@163.com. FAU - Qiu, Zhi-Xia AU - Qiu ZX AD - School of Pharmacy, China Pharmaceutical University, Nanjing, 211198, China. qiuzhixia_cpu@163.com. LA - eng PT - Journal Article DEP - 20201007 PL - United States TA - Acta Pharmacol Sin JT - Acta pharmacologica Sinica JID - 100956087 RN - 0 (Abietanes) RN - 0 (Anti-Inflammatory Agents) RN - 0 (Enzyme Inhibitors) RN - 0 (Hif1a protein, mouse) RN - 0 (Hypoxia-Inducible Factor 1, alpha Subunit) RN - 0 (Inflammasomes) RN - 0 (Lipopolysaccharides) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (Nlrp3 protein, mouse) RN - 0 (Reactive Oxygen Species) RN - 0 (Tubulin) RN - 03UUH3J385 (tanshinone) RN - EC 1.3.99.1 (SDHD protein, mouse) RN - EC 1.3.99.1 (Succinate Dehydrogenase) RN - EC 3.5.1.- (Sirt2 protein, mouse) RN - EC 3.5.1.- (Sirtuin 2) SB - IM MH - Abietanes/*therapeutic use MH - Acetylation/drug effects MH - Animals MH - Anti-Inflammatory Agents/*therapeutic use MH - Enzyme Inhibitors/*therapeutic use MH - Glycolysis/drug effects MH - Hypoxia-Inducible Factor 1, alpha Subunit/metabolism MH - Inflammasomes/metabolism MH - Inflammation/chemically induced/metabolism/*prevention & control MH - Lipopolysaccharides MH - Macrophages/*drug effects MH - Male MH - Mice, Inbred C57BL MH - NLR Family, Pyrin Domain-Containing 3 Protein/metabolism MH - Reactive Oxygen Species/metabolism MH - Sirtuin 2/metabolism MH - Succinate Dehydrogenase/*antagonists & inhibitors MH - Tubulin/metabolism MH - Mice PMC - PMC8149828 OTO - NOTNLM OT - HIF-1alpha OT - NLRP3 inflammasome OT - SDH OT - Sirt2 OT - lipopolysaccharides OT - macrophages OT - succinate OT - tanshinone IIA COIS- The authors declare no competing interests. EDAT- 2020/10/09 06:00 MHDA- 2021/10/08 06:00 PMCR- 2022/06/01 CRDT- 2020/10/08 05:30 PHST- 2019/12/31 00:00 [received] PHST- 2020/09/10 00:00 [accepted] PHST- 2020/10/09 06:00 [pubmed] PHST- 2021/10/08 06:00 [medline] PHST- 2020/10/08 05:30 [entrez] PHST- 2022/06/01 00:00 [pmc-release] AID - 10.1038/s41401-020-00535-x [pii] AID - 535 [pii] AID - 10.1038/s41401-020-00535-x [doi] PST - ppublish SO - Acta Pharmacol Sin. 2021 Jun;42(6):987-997. doi: 10.1038/s41401-020-00535-x. Epub 2020 Oct 7.