PMID- 37468929 OWN - NLM STAT- MEDLINE DCOM- 20230721 LR - 20230725 IS - 1478-6362 (Electronic) IS - 1478-6354 (Print) IS - 1478-6354 (Linking) VI - 25 IP - 1 DP - 2023 Jul 19 TI - Sirt3 improves monosodium urate crystal-induced inflammation by suppressing Acod1 expression. PG - 121 LID - 10.1186/s13075-023-03107-6 [doi] LID - 121 AB - BACKGROUND: Previous studies have revealed that Sirt3 deficiency is associated with several inflammatory responses. The purpose of this study is to investigate the role and potential molecular mechanisms of Sirt3 in the inflammation induced by monosodium urate (MSU) crystals. METHODS: The Sirt3 expression level in the peripheral blood mononuclear cells (PBMCs) of patients with gout was measured. Function and molecular mechanism of Sirt3 in MSU crystal-induced inflammation were investigated in bone marrow-derived macrophages (BMDMs), C57BL/6 mouse, and Sirt3(-/-) mouse. RESULTS: Sirt3 expression was decreased in the PBMCs of patients with gout. Sirt3 agonist (Viniferin) inhibited the acetylation levels of mitochondrial proteins including the SOD2 protein. RNA sequencing, bio-informatics analysis, RT-PCR, and Western blot demonstrated that Sirt3 could suppress the expression of Acod1 (Irg1), which plays an important role in gout. In BMDMs treated with palmitic acid (C16:0) plus MSU crystals, Acod1 knockdown repressed mitochondrial reactive oxygen species (mtROS) over-production, macrophage migration, and mitochondrial fragmentation, and Acod1 improved AMPK activity. The over-expression of Acod1 did not significantly affect the level of itaconic acid, but greatly decreased the levels of some important intermediate metabolites of the tricarboxylic acid (TCA) cycle. These data indicate that Acod1 exerts a pro-inflammatory role in MSU crystal-induced inflammation and is independent of the metabolic level of itaconic acid. Sirt3 deficiency exacerbates inflammatory response induced by MSU crystals in vitro and in vivo. CONCLUSION: The current study has shown that Sirt3 can alleviate the MSU crystal-induced inflammation by inhibiting the expression of Acod1. CI - (c) 2023. The Author(s). FAU - Lv, Linxi AU - Lv L AD - Institute of Rheumatology and Immunology, the Affiliated Hospital of North Sichuan Medical College, 1# South Maoyuan Road, Nanchong, 637001, Sichuan, China. FAU - Jiang, Hui AU - Jiang H AD - Institute of Rheumatology and Immunology, the Affiliated Hospital of North Sichuan Medical College, 1# South Maoyuan Road, Nanchong, 637001, Sichuan, China. FAU - Song, Dianze AU - Song D AD - Institute of Rheumatology and Immunology, the Affiliated Hospital of North Sichuan Medical College, 1# South Maoyuan Road, Nanchong, 637001, Sichuan, China. AD - Medical Imaging Key Laboratory of Sichuan Province, the Affiliated Hospital of North Sichuan Medical College, 1# South Maoyuan Road, Nanchong, 637001, Sichuan, China. AD - Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, 234# Fujiang Road, Nanchong, 637000, Sichuan Province, China. FAU - Zhou, Xiaoqin AU - Zhou X AD - Institute of Rheumatology and Immunology, the Affiliated Hospital of North Sichuan Medical College, 1# South Maoyuan Road, Nanchong, 637001, Sichuan, China. FAU - Chen, Feng AU - Chen F AD - Institute of Rheumatology and Immunology, the Affiliated Hospital of North Sichuan Medical College, 1# South Maoyuan Road, Nanchong, 637001, Sichuan, China. AD - Medical Imaging Key Laboratory of Sichuan Province, the Affiliated Hospital of North Sichuan Medical College, 1# South Maoyuan Road, Nanchong, 637001, Sichuan, China. AD - Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, 234# Fujiang Road, Nanchong, 637000, Sichuan Province, China. FAU - Ren, Long AU - Ren L AD - The Fifth People's Hospital of Nanchong City, 21# Bajiao Street, Nanchong, 637100, Sichuan, China. FAU - Xie, Yongen AU - Xie Y AD - Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, 234# Fujiang Road, Nanchong, 637000, Sichuan Province, China. FAU - Zeng, Mei AU - Zeng M AD - Institute of Rheumatology and Immunology, the Affiliated Hospital of North Sichuan Medical College, 1# South Maoyuan Road, Nanchong, 637001, Sichuan, China. zengmei123@nsmc.edu.cn. AD - Medical Imaging Key Laboratory of Sichuan Province, the Affiliated Hospital of North Sichuan Medical College, 1# South Maoyuan Road, Nanchong, 637001, Sichuan, China. zengmei123@nsmc.edu.cn. AD - Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, 234# Fujiang Road, Nanchong, 637000, Sichuan Province, China. zengmei123@nsmc.edu.cn. AD - The Fifth People's Hospital of Nanchong City, 21# Bajiao Street, Nanchong, 637100, Sichuan, China. zengmei123@nsmc.edu.cn. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230719 PL - England TA - Arthritis Res Ther JT - Arthritis research & therapy JID - 101154438 RN - Q4516562YH (itaconic acid) RN - 0 (Sirt3 protein, mouse) RN - EC 3.5.1.- (Sirtuin 3) RN - 268B43MJ25 (Uric Acid) RN - EC 4.1.1.6 (aconitate decarboxylase) SB - IM MH - Animals MH - Mice MH - *Gout/chemically induced/drug therapy/metabolism MH - Inflammation/chemically induced/metabolism MH - Leukocytes, Mononuclear/metabolism MH - Mice, Inbred C57BL MH - *Sirtuin 3/genetics/metabolism MH - Uric Acid/toxicity PMC - PMC10354977 OTO - NOTNLM OT - Acod1 OT - MSU crystals OT - SOD2 acetylation level OT - Sirt3 OT - TCA cycle COIS- The authors declare no competing interests. EDAT- 2023/07/20 01:07 MHDA- 2023/07/21 06:44 PMCR- 2023/07/19 CRDT- 2023/07/19 23:45 PHST- 2023/03/24 00:00 [received] PHST- 2023/07/05 00:00 [accepted] PHST- 2023/07/21 06:44 [medline] PHST- 2023/07/20 01:07 [pubmed] PHST- 2023/07/19 23:45 [entrez] PHST- 2023/07/19 00:00 [pmc-release] AID - 10.1186/s13075-023-03107-6 [pii] AID - 3107 [pii] AID - 10.1186/s13075-023-03107-6 [doi] PST - epublish SO - Arthritis Res Ther. 2023 Jul 19;25(1):121. doi: 10.1186/s13075-023-03107-6.