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Sirtuin 5 deficiency increases disease severity in rats with adjuvant-induced arthritis

Cellular & Molecular Immunology volume 17, pages 1190–1192 (2020)Cite this article

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The influence of inflammatory stimuli on SIRT5 expression was further examined by using RA patient-derived synovial fibroblasts (RASFs) in the presence of MTX, suramin (a SIRT5 inhibitor), Toll-like receptor ligands such as lipopolysaccharides (LPS), Pam, and poly (I:C), and the proinflammatory cytokines TNF-α and IL-1β. As shown in Fig. 1e, suramin suppressed SIRT5 expression and markedly abolished MTX-stimulated expression of SIRT5 in RASFs, while RASFs treated with Toll-like receptor ligands and proinflammatory cytokines downregulated SIRT5 expression (Fig. 1f). In purified human CD14+CD16− monocytes, overexpression of SIRT5 abolished LPS-mediated release of IL-6 and TNF-α, whereas the addition of suramin partially blocked the inhibitory effect of SIRT5 (Fig. 1g). In contrast, knockdown of SIRT5 significantly enhanced the LPS-mediated release of IL-1β and TNF-α in CD14+CD16− monocytes (Fig. 1h). The anti-inflammatory role of SIRT5 was further characterized by injection of adenovirus-SIRT5 (Ad-SIRT5) into the ankle joints of AIA rats. While severe swelling, erythema and joint rigidity developed in the hind paws of AIA rats that were injected with Ad-EGFP virus (vehicle control), the arthritic scores and hind paw volumes were significantly attenuated in rats that were injected with either a single dose or double doses of Ad-SIRT5 (1 × 1011 PFU) (Fig. 1i–l). However, the SIRT5 mutant SIRT5H158Y,4 failed to attenuate the arthritic condition in AIA rats, suggesting that the deacetylation and desuccinylation activity of SIRT5 contributes to the anti-inflammatory effects of SIRT5 in RA. Notably, AIA rats that were injected with double doses of Ad-SIRT5 (1 × 1011 PFU) exhibited significant recovery in the masses of the spleen and thymus, indicating the suppression of spleen enlargement and prevention of thymus shrinkage, compared with those of vehicle-treated animals (Supplementary Fig. S1B–D). These findings suggest that the amelioration of inflammatory conditions in AIA rats is closely associated with the recovery of immune organ functions in animals.

Microcomputed tomography (micro-CT) and histopathological analysis further indicated the typical symptoms of swollen joints, bone destruction, synovial membrane hyperplasia with severe inflammatory cell infiltration, and pannus formation in joint tissues of Ad-EGFP vehicle and Ad-SIRT5H158Y mutant rats (Fig. 1k, l). Notably, infiltration of inflammatory cells and hyperplasia of articular cartridge were ameliorated in AIA rats that were injected with low-dose (3 × 109 PFU), single-dose, and double-dose Ad-SIRT5 (1 × 1011 PFU) or were treated with MTX (Fig. 1k, l), whereas immunofluorescence staining of the synovial tissues further showed the increasing trend in SIRT5 expression and the reduced level of vimentin, representing the low proliferative rate of synovial fibroblasts5 (Fig. 1m). Micro-CT analysis of bone mineral density, bone volume fraction, cortical mineral density (TMD), trabecular number, and total porosity of Ad-SIRT5-treated AIA rats showed that the mean micro-CT score increased significantly from 0.26 (Ad-EGFP vehicle control) to 0.70 [Ad-SIRT5 (1 × 1011 PFU)] (Supplementary Fig. S2A, B), and the mean radiological score dropped from 4.0 to 0.42 for these same groups (Supplementary Fig. S2C). In addition, the animals that were treated with MTX and high-dose Ad-SIRT5 showed significant suppression of the proinflammatory cytokines monocyte chemoattractant protein-1 (MCP-1), TNF-α, IL-1β, and IL-6, with a concomitant reduction in erythrocyte sedimentation rate and C-reactive protein levels in blood serum (Supplementary Fig. S3A). Collectively, these results validated the potential anti-inflammatory role of SIRT5 in AIA rats.

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Fig. 1: The anti-inflammatory role of SIRT5 in RA.

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Funding

This work was supported by a FDCT grant from the Macao Science and Technology Development Fund (Project code: 0048/2018/A2), FDCT grant from the Macao Science and Technology Development Fund (Project code:0003/2019/AKP), and the Foshan Medicine Dengfeng Project of China (2019–2021).

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  1. State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, China

    Ni Zhang, Hui Zhang, Betty Yuen Kwan Law, Ivo Ricardo De Seabra Rodrigues Dias, Cong Ling Qiu, Wu Zeng, Hu Dan Pan, Li Qun Qu, Xi Chen, Qi Huang, Wei Zhang, Li Jun Yang, Lu Yu, Yu Han, Guo Xin Huang, Hui Miao Wang, Xiao Lei Sun, Yun Zhang, Hu Qiang He, Wei Dan Luo, Yao Xiao, Vincent Kam Wai Wong & Liang Liu

  2. The Third Affiliated Hospital of Soochow University, Changzhou, Jiangsu, China

    Jin Yun Chen, Ting Xu & Min Wu

  3. Guangzhou Hospital of Integrated Traditional Chinese and Western Medicine, Guangzhou, China

    Yan Fu Bai & Zhi Sheng Huang

  4. Department of Rheumatology and Immunology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China

    Jing Lv & Wei Liu

  5. School of Pharmaceutical Sciences, Traditional Chinese Medicine University of Guangzhou, Guangzhou, China

    Jian Zhou

  6. Department of Rheumatology, Guangdong Hospital of Traditional Chinese Medicine, Guangzhou, China

    Qing Chun Huang

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Correspondence to Vincent Kam Wai Wong or Liang Liu.

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Blood samples were collected from patients with RA and OA and healthy volunteers who provided signed informed and voluntary consent in Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou (China), and with the approval of the Research Ethics Committee (GDREC 2015391H). Animal care and experimental procedures were approved and conducted under the guide for the Laboratory Animal Research Committee Guidelines of Guangzhou, University of Chinese Medicine, and ethics approval by the Macau University of Science and Technology, Medical Ethics Committee, Macau (China).

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Zhang, N., Zhang, H., Law, B.Y.K. et al. Sirtuin 5 deficiency increases disease severity in rats with adjuvant-induced arthritis. Cell Mol Immunol 17, 1190–1192 (2020). https://doi.org/10.1038/s41423-020-0380-4

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