Regulation and function of SIRT1 in rheumatoid arthritis synovial fibroblasts

Abstract

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and destruction of synovial joints. The function of sirtuin (SIRT)1 in RA is inconclusive. In human synovial cells, SIRT1 was shown to promote cytokine production and apoptosis resistance. However, deletion of SIRT1 aggravated inflammatory arthritis in mice and increased production of pro-inflammatory cytokines in murine macrophages. In the current study, we investigated the regulation, expression, and function of SIRT1 in RA, in particular its role in adhesion and proliferation of human RA synovial fibroblasts (RASF). We found that expression of SIRT1 was increased in vivo in synovial tissues of RA smokers and in vitro by stimulation of RASF with TNF, but decreased upon treatment with cigarette smoke extract. Synovial tissues of RA smokers showed higher leukocytic infiltration that positively correlated with enhanced levels of SIRT1. Global transcriptome analysis revealed that SIRT1 modulates expression of genes involved in the regulation of inflammatory response and cell adhesion. In functional studies, silencing of SIRT1 reduced proliferation and leukocytic adhesion to RASF but showed inconsistent results in the regulation of adhesion to plastic. In conclusion, SIRT1 modulates the proliferative and potentially also adhesive properties of RASF and can therefore promote progression of RA. KEY MESSAGES: SIRT1 is upregulated by TNF but decreased upon CSE treatment of RASF. Upregulation of SIRT1 in RA smokers correlates with increased leukocytic infiltration. SIRT1 modulates expression of genes regulating cell adhesion and inflammation. SIRT1 regulates proliferation of RASF. AbstractRheumatoid arthritis (RA) is a chronic autoimmune disease characterized by inflammation and destruction of synovial joints. The function of sirtuin (SIRT)1 in RA is inconclusive. In human synovial cells SIRT1 was shown to promote cytokine production and apoptosis resistance. However, deletion of SIRT1 aggravated inflammatory arthritis in mice and increased production of pro-inflammatory cytokines in murine macrophages. In the current study we investigated the regulation, expression and function of SIRT1 in RA, in particular its role in adhesion and proliferation of human RA synovial fibroblasts (RASF). We found that expression of SIRT1 was increased in vivo in synovial tissues of RA smokers and in vitro by stimulation of RASF with TNFα, but decreased upon treatment with cigarette smoke extract.Synovial tissues of RA smokers showed higher leukocytic infiltration that positively correlated with enhanced levels of SIRT1. Global transcriptome analysis revealed that SIRT1modulates expression of genes involved in the regulation of inflammatory response and cell adhesion. In functional studies, silencing of SIRT1 reduced proliferation and leukocytic adhesion to RASF, but showed inconsistent results in the regulation of adhesion to plastic. In conclusion, SIRT1 modulates the proliferative and potentially also adhesive properties of RASF and can t...

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

“…It has been argued SIRT1 aggravates inflammation by upregulating the expressions of pro-inflammatory cytokines in synovial fibroblasts ( 19 ) and in the synovial tissues of smokers with RA ( 35 ). Nevertheless, Wendling et al ( 17 ) have revealed that SIRT1 expression and its activity in the cytoplasm of PBMCs from RA patients are lower than in healthy controls.…”

SIRT1 promotes tumor-like invasion of fibroblast-like synoviocytes in rheumatoid arthritis via targeting TIMP1

“…Silent information regulator 2 homolog1 (SIRT1), a NAD-dependent histone deacetylase, is involved in the pathogenesis of cancer [ 24 ], metabolic disease [ 25 ], inflammation [ 26 ] and arthritis [ 27 ]. The roles of SIRT1 in RA are mainly focused on the immune response [ 4 – 6 ], the proliferation and adhesion of RA FLSs [ 7 ]. To the best of our knowledge, there are no reports concerning the effect of SIRT1 on FLS invasion and joint destruction.…”

“…Moreover, myeloid deletion of SIRT1 inhibited dendritic cell maturation and further alleviated arthritis in collagen-induced arthritis (CIA) mice [ 6 ]. In addition, SIRT1 contributed to FLS proliferation and adhesion during RA progression [ 7 ].…”

Exploring Epigenetic Drugs in the Regulation of Inflammatory Autoimmune Diseases

“…On the other hand, HDAC class III enzymes showed a contradictory function in RA. For example, the levels of the NAD-dependent protein deacetylase SIRT6 are increased in the joint tissues of collagen-induced arthritis (CIA) in mice, and further studies revealed that SIRT6 overexpression attenuates the severity of arthritis by reducing both the inflammatory response and tissue destruction, whereas SIRT1 levels were increased and its overexpression contributed inflammatory cytokine production [88,89]. Finally, Pan-inhibitors against the BET protein family (acetylation readers) have anti-inflammatory and anti-destructive properties in vitro [90] and in CIA mice [91,92].…”