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SIRT1 inhibits differentiation of monocytes to macrophages: amelioration of synovial inflammation in rheumatoid arthritis

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Abstract

Monocyte-to-macrophage differentiation plays a central role in the pathophysiology of rheumatoid arthritis (RA)-associated inflammation because it results in the secretions of various inflammatory mediators in inflamed synovium, and thus, this differentiation is viewed as a clinical target. We aimed to determine whether SIRT1 inhibits the differentiation of monocytes from RA patients into macrophages by suppressing PU.1 phosphorylation. Monocytes from synovial fluid of RA patients (RAMCs), THP-1 monocytes, and mouse bone marrow-derived monocytes (BMDCs) were studied. The phorbol 12-myristate 13-acetate (PMA)-stimulated RA monocyte adherence was significantly inhibited by resveratrol (a SIRT1 activator), and this inhibition by resveratrol was prevented by pretreating cells with sirtinol (a SIRT1 inhibitor). Furthermore, resveratrol pretreatment inhibited PMA-induced expressions of macrophage surface markers (CD11b, CD14, and CD36) and PMA-induced NF-κB transcriptional activation and, thus, suppressed the secretions of proinflammatory cytokines (TNF-α, IL-1β, and IL-6). In SIRT1 transgenic (Tg) mice, monocyte differentiation was inhibited and NF-κB transcriptional activity was suppressed and the expressions of TNF-α, IL-1β, and IL-6 were decreased at the protein and mRNA levels versus control C57BL/6 mice. Furthermore, SIRT1 activation by resveratrol suppressed PMA-induced phosphorylation and the nuclear translocation of PU.1 and, thus, inhibited monocyte differentiation. In conclusion, SIRT1 appears to inhibit monocyte to macrophage differentiation by suppressing PU.1 phosphorylation and inflammatory signaling, which suggests SIRT1 plays a critical role in the regulation of synovial inflammation in RA.

Key message

  • SIRT1 overexpression inhibits monocyte to macrophage differentiation.

  • SIRT1 suppresses PU.1 phosphorylation.

  • Inactivation of PU.1 phosphorylation inhibits monocyte differentiation.

  • SIRT1 regulates inflammation by inhibiting NF-κB during monocyte differentiation.

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Acknowledgments

This work was supported by the National Research Foundation of Korea (Grant no. NRF-2013R1A1A2057741) and by the Medical Research Center (MRC) Program through National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (Grant no. NRF-2015R1A5A2009656).

The authors would like to thank Dr. J.W. Park (Seoul National University, Korea) for providing the SIRT1 Tg mice.

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Authors and Affiliations

  1. Gene & Cell Therapy Research Center for Vessel-associated Diseases, Pusan National University, Yangsan-si, Gyeongsangnam-do, 50612, Republic of Korea

    So Youn Park, Hye Young Kim, Ki Whan Hong & Chi Dae Kim

  2. Department of Internal Medicine, College of Medicine, Dong-A University, Busan, 49202, Republic of Korea

    Sung Won Lee & Sang Yeob Lee

  3. Department of Pharmacology, School of Medicine, Pusan National University, Yangsan-si, Gyeongsangnam-do, 50612, Republic of Korea

    Won Suk Lee & Chi Dae Kim

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  1. So Youn Park
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Correspondence to Chi Dae Kim.

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Park, S.Y., Lee, S.W., Kim, H.Y. et al. SIRT1 inhibits differentiation of monocytes to macrophages: amelioration of synovial inflammation in rheumatoid arthritis. J Mol Med 94, 921–931 (2016). https://doi.org/10.1007/s00109-016-1402-7

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  • DOI: https://doi.org/10.1007/s00109-016-1402-7

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