SIRT1/Adenosine Monophosphate-Activated Protein Kinase α Signaling Enhances Macrophage Polarization to an Anti-inflammatory Phenotype in Rheumatoid Arthritis

Frontiers in Immunology

Sang Yeob Lee¹  Sung Won Lee¹  Koanhoi Kim²  So Youn Park³  Ki Whan Hong³  Chi Dae Kim³  Sun Sik Bae³ 

[1] Department of Internal Medicine, College of Medicine, Dong-A University, Busan, South Korea;Department of Pharmacology, School of Medicine, Pusan National University, Gyeongsangnam-do, South Korea;Gene and Cell Therapy Research Center for Vessel-Associated Diseases, Pusan National University, Gyeongsangnam-do, South Korea;

关键词: rheumatoid arthritis;    inflammation;    macrophage polarization;    M1/M2 macrophages;    SIRT1;    adenosine monophosphate-activated protein kinase α;   

DOI  :  10.3389/fimmu.2017.01135

来源: DOAJ

【 摘 要 】

Macrophages are crucially involved in the pathogenesis of rheumatoid arthritis (RA). Macrophages of the M1 phenotype act as pro-inflammatory mediators in synovium, whereas those of the M2 phenotype suppress inflammation and promote tissue repair. SIRT1 is a class 3 histone deacetylase with anti-inflammatory characteristics. However, the role played by SIRT1 in macrophage polarization has not been defined in RA. We investigated whether SIRT1 exerts anti-inflammatory effects by modulating M1/M2 polarization in macrophages from RA patients. In this study, SIRT1 activation promoted the phosphorylation of an adenosine monophosphate-activated protein kinase (AMPK) α/acetyl-CoA carboxylase in macrophages exposed to interleukin (IL)-4, and that this resulted in the expressions of M2 genes, including MDC, FcεRII, MrC1, and IL-10, at high levels. Furthermore, these expressions were inhibited by sirtinol (an inhibitor of SIRT1) and compound C (an inhibitor of AMPK). Moreover, SIRT1 activation downregulated LPS/interferon γ-mediated NF-κB activity by inhibiting p65 acetylation and the expression of M1 genes, such as CCL2, iNOS, IL-12 p35, and IL-12 p40. Macrophages from SIRT1 transgenic (Tg)-mice exhibited enhanced polarization of M2 phenotype macrophages and reduced polarization of M1 phenotype macrophages. In line with these observations, SIRT1-Tg mice showed less histological signs of arthritis, that is, lower TNFα and IL-1β expressions and less severe arthritis in the knee joints, compared to wild-type mice. Taken together, the study shows activation of SIRT1/AMPKα signaling exerts anti-inflammatory activities by regulating M1/M2 polarization, and thereby reduces inflammatory responses in RA. Furthermore, it suggests that SIRT1 signaling be viewed as a therapeutic target in RA.

【 授权许可】

Unknown