Abstract
Activated rheumatoid arthritis (RA) synovial fibroblasts (SFs) are among the most important cells promoting RA pathogenesis. They are considered active contributors to the initiation, progression, and perpetuation of the disease; therefore, early detection of RASF activation could advance contemporary diagnosis and adequate treatment of undifferentiated early inflammatory arthritis (EA). In this study, we investigated the expression of nucleotide-binding, oligomerization domain (NOD)-like receptor family, pyrin domain containing (NLRP)1, NLRP3 inflammasomes, Toll-like receptor (TLR)1, TLR2, TLR4, vitamin D receptor (VDR), and secretion of matrix metalloproteinases (MMPs) in SFs isolated from patients with RA, osteoarthritis (OA), EA, and control individuals (CN) after knee surgical intervention. C-reactive protein, general blood test, anticyclic citrullinated peptide (anti-CCP), rheumatoid factor (RF), and vitamin D (vitD) in patients’ sera were performed. Cells were stimulated or not with 100 ng/ml tumor necrosis factor alpha (TNF-α) or/and 1 nM or/and 0.01 nM vitamin D3 for 72 h. The expression levels of NLRP1, NLRP3, TLR1, TLR2, TLR4, and VDR in all examined SFs were analyzed by quantitative real-time PCR (RT-qPCR). Additionally, the secretion of IL-1β by SFs and MMPs were determined by ELISA and Luminex technology. The expression of NLRP3 was correlated with the levels of CRP, RF, and anti-CCP, suggesting its implication in SF inflammatory activation. In the TNF-α-stimulated SFs, a significantly lower expression of NLRP3 and TLR4 was observed in the RA group, compared with the other tested forms of arthritis. Moreover, upregulation of NLRP3 expression by TNF-α alone or in combination with vitD3 was observed, further indicating involvement of NLRP3 in the inflammatory responses of SFs. Secretion of IL-1β was not detected in any sample, while TNF-α upregulated the levels of secreted MMP-1, MMP-7, MMP-8, MMP-12, and MMP-13 in all patient groups. Attenuating effects of vitD on the expression of NLRP3, TLR1, and TLR4 suggest potential protective effects of vitD on the inflammatory responses in SFs. However, longer studies may be needed to confirm or fully rule out the potential implication of vitD in SF activation in inflammatory arthritis. Both VDR and NLRP3 in the TNF-α-stimulated SFs negatively correlated with the age of patients, suggesting potential age-related changes in the local inflammatory responses.
Highlights
Onset of inflammatory arthritis is a rheumatic condition that has different outcomes, as reported in different cohort studies: up to 20%–60% of patients will resolve completely even without any treatment, 13%–54% of patients with undifferentiated arthritis (UA) will develop rheumatoid arthritis (RA), 21%–87% UA will persist after 1 year [1]
Long-term acute inflammation-related phenotypic changes in rheumatoid arthritis synovial fibroblast (RASF) lead to pannus formation and increased cartilage and bone tissue degradation [12, 49]
Pathological reactions might arise from the inappropriate response of the receptor, for instance, Toll-like receptor (TLR) or nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing (NLRP), due to their particular genetic background or to the inappropriate quantity or quality of ligands [52]
Summary
Onset of inflammatory arthritis is a rheumatic condition that has different outcomes, as reported in different cohort studies: up to 20%–60% of patients will resolve completely even without any treatment, 13%–54% of patients with undifferentiated arthritis (UA) will develop rheumatoid arthritis (RA), 21%–87% UA will persist after 1 year [1]. Patients with positive rheumatoid factor (RF) and/or anticyclic citrullinated peptide (anti-CCP) and/or C-reactive protein (CRP) are known to be at increased risk of developing worse prognosis of erosive arthritis, the main clinical manifestation of which is synovitis [4]. Anti-CCP is known to be one of most sensitive and specific RA diagnostic markers (sensitivity 92.70 [90.67–94.74] and specificity 79.93 [72.44–87.42]) [5]. It can be found positive in other diseases, for instance, approximately 5% of patients with psoriatic arthritis are anti-CCP positive [6, 7]. Anti-CCP can be detected as positive in autoimmune hepatitis-1, biliary cirrhosis, hepatitis C virusrelated disease, Sjögren’s syndrome (SS), palindromic
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