SIRT6 regulates the cigarette smoke-induced signalling in rheumatoid arthritis synovial fibroblasts

Cigarette smoking is a recognized environmental risk factor for the development and progression of rheumatoid arthritis (RA). RA synovial fibroblasts (RASF) actively contribute to inflammation and joint destruction in this chronic inflammatory autoimmune disease. In the current study, we investigated the influence of cigarette smoke on the inflammatory and matrix-destructive properties of RASF. Furthermore, the functional role of Sirtuin 6 (SIRT6) in the regulation of the signalling induced by cigarette smoke or by tumor necrosis factor alpha (TNFα) was elucidated. We demonstrated that stimulation with cigarette smoke extract (CSE) enhances the pro-inflammatory and matrix-destructive potential of RASF by inducing the production of pro-inflammatory cytokine interleukin 8 (IL8) and the matrix-destructive enzyme matrix metalloproteinase 1 (MMP1), but not of IL6 and MMP3. Moreover, we could show that the expression of MMP1 is specifically regulated by SIRT6. Treatment of RASF with CSE or TNFα increased the levels of SIRT6. The expression of SIRT6 was also enhanced in vivo in synovial tissues of RA smokers and in joints of mice exposed to cigarette smoke. Silencing of SIRT6 specifically increased basal as well as CSE- and TNFα-induced production of MMP1, demonstrating that SIRT6 plays an important role in restricting MMP1 expression. In conclusion, the upregulation of SIRT6 in RASF under CSE or TNFα stimulation functions as a counterregulatory mechanism attenuating the production of the matrix-destructive enzyme MMP1. This is the first study revealing the protective function of SIRT6 in the cigarette smoke-induced signalling. KEY MESSAGES: Cigarette smoke induces pro-inflammatory and matrix-destructive responses in RASF. Cigarette smoke enhances the expression of SIRT6 in vitro and in vivo. TNFα increases the levels of SIRT6. SIRT6 diminishes MMP1 production under cigarette smoke extract and TNFα stimulation

Circulating secretory IgA antibodies against cyclic citrullinated peptides in early rheumatoid arthritis associate with inflammatory activity and smoking

Background: A possible association between mucosal immunization and inflammation, as well as the initiation and propagation of rheumatoid arthritis (RA), is attracting renewed interest. The aim of this study was to evaluate the possible occurrence and clinical correlations of circulating secretory immunoglobulin A (SIgA) antibodies against the second-generation cyclic citrullinated peptides (CCP) among patients with recent-onset RA followed prospectively over 3 years. Methods: Baseline serum samples from 636 patients with recent-onset RA were analyzed for SIgA anti-CCP antibodies by using an enzyme-linked immunosorbent assay with a secondary antibody directed against secretory component. SIgA anti-CCP status at baseline was analyzed in relation to smoking, HLA-DRB1/shared epitope (SE), and the disease course over 3 years. Significant findings were evaluated in regression analysis that included age, sex, smoking, and SE. Results: Seventeen percent of the patients tested positive for circulating SIgA anti-CCP, and the occurrence was confirmed by detection of secretory component in an affinity-purified IgA anti-CCP fraction. SIgA anti-CCP positivity at baseline was associated with slightly higher baseline erythrocyte sedimentation rate (ESR) (mean 38 vs. 31 mm/first hour, p = 0.004) and C-reactive protein (CRP) (mean 30 vs. 23 mg/L, p = 0.047). During follow-up, SIgA anti-CCP-positive patients had a higher mean AUC regarding ESR (adjusted p = 0.003), although there were no significant differences regarding CRP, tender and swollen joint counts, or radiological joint damage (median Larsen progression 1.0 vs. 1.0, p = 0.22). SIgA anti-CCP was associated significantly with smoking (79 % ever smokers among SIgA anti-CCP-positive patients vs. 59 % in SIgA anti-CCP-negative patients, adjusted OR 2.19, 95 % CI 1.01-4.37, p = 0.027) but not with carriage of the SE (80 % vs. 73 %, p = 0.62). Conclusions: Circulating SIgA anti-CCP, which is present in a subgroup of patients with early RA, is not related to SE, but it is environmentally linked to cigarette smoking. This finding strengthens the hypothesis that immunization against citrullinated peptides and/or proteins may occur at mucosal surfaces of the airways. Analysis of SIgA antibodies in serum may be a convenient and more versatile means to investigate the "mucosal connection" in RA compared with analyses in mucosal fluid samples.Funding Agencies|King Gustav Vs 80-year Foundation; Swedish Medical Society; Reinhold Sund Foundation; Ostergotland County Council</p

Regulation and function of SIRT1 in rheumatoid arthritis synovial fibroblasts

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 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 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 TNFα 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