2. Academic Validation
  3. Sirt3 improves monosodium urate crystal-induced inflammation by suppressing Acod1 expression

Sirt3 improves monosodium urate crystal-induced inflammation by suppressing Acod1 expression

  • Arthritis Res Ther. 2023 Jul 19;25(1):121. doi: 10.1186/s13075-023-03107-6.
Linxi Lv # 1,  Hui Jiang # 1,  Dianze Song 1 2 3,  Xiaoqin Zhou 1,  Feng Chen 1 2 3,  Long Ren 4,  Yongen Xie 3,  Mei Zeng 5 6 7 8
Affiliations

Affiliations

  • 1 Institute of Rheumatology and Immunology, the Affiliated Hospital of North Sichuan Medical College, 1# South Maoyuan Road, Nanchong, 637001, Sichuan, China.
  • 2 Medical Imaging Key Laboratory of Sichuan Province, the Affiliated Hospital of North Sichuan Medical College, 1# South Maoyuan Road, Nanchong, 637001, Sichuan, China.
  • 3 Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, 234# Fujiang Road, Nanchong, 637000, Sichuan Province, China.
  • 4 The Fifth People's Hospital of Nanchong City, 21# Bajiao Street, Nanchong, 637100, Sichuan, China.
  • 5 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.
  • 6 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.
  • 7 Institute of Basic Medicine and Forensic Medicine, North Sichuan Medical College, 234# Fujiang Road, Nanchong, 637000, Sichuan Province, China. zengmei123@nsmc.edu.cn.
  • 8 The Fifth People's Hospital of Nanchong City, 21# Bajiao Street, Nanchong, 637100, Sichuan, China. zengmei123@nsmc.edu.cn.
  • # Contributed equally.
PMID: 37468929 DOI: 10.1186/s13075-023-03107-6
Abstract

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.

Keywords

Acod1; MSU crystals; SOD2 acetylation level; Sirt3; TCA cycle.

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