Toll-Like Receptors Expressed by Synovial Fibroblasts Perpetuate Th1 and Th17 Cell Responses in Rheumatoid Arthritis

Abstract

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial fibroblast hyperplasia and bone and cartilage erosion. Synovial fibroblast- and T cell-mediated inflammation plays crucial roles in the pathogenesis of RA. However how this inflammation is initiated, propagated, and maintained remains controversial. Here, we systemically examined the contribution of toll-like receptors (TLRs) to the inflammatory mediator production as well as Th1 and Th17 cell hyperactivity in RA. Our results show that rheumatoid arthritis synovial fibroblasts (RASF) express a series of TLRs, including TLR2, TLR3, TLR4, and TLR9, with the predominant expression of TLR3. Moreover, the expression levels of these TLRs were higher than those in osteoarthritis synovial fibroblasts (OASF). Ligation of TLR3, as well as TLR2 and TLR4, resulted in vigorous production of inflammatory cytokines, matrix metalloproteinases (MMPs), and vascular endothelial growth factor (VEGF) in RASF, with activation of the NF-κB, MAPK, and IRF3 pathways. More important, activation of these TLRs expressed by RASF exacerbated inflammatory Th1 and Th17 cell expansion both in cell-cell contact-dependent and inflammatory cytokine-dependent manners, which induced more IFN-γ and IL-17 accumulation. Targeting TLRs may modulate the inflammation in RA and provide new therapeutic strategies for overcoming this persistent disease.

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“…IL-17 and TNF promote fibroblast and chondrocyte activation that is related to the pathogenesis of RA (Hu et al 2014). Further, IL-17 acts on the differentiation of osteoclasts and bone reabsorption and, in monocytes, stimulates the production of TNF and IL-1β (Chen et al 2011).…”

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“…35 In RA, IL-17 induces synoviocyte hyperplasia and production of pro-inflammatory mediators to promote TLRdependent joint damage and pro-inflammatory infiltration, maturation and survival of neutrophils as well as that of T and B lymphocytes, which organize themselves in ectopic follicular-like structures with germinal centres to perpetuate local inflammation. [36][37][38][39] Excitingly, ES-62-treated mice undergoing CIA showed reduced levels of IL-17 compared to control animals. 24 In line with the observed correlation of elevated serum IL-17 levels with disease activity in RA patients, 39 ES-62 not only reduced the levels of IL-17 in serum derived from mice with CIA but also those in the draining lymph nodes and joints.…”

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“…In rheumatoid arthritis (RA), which is a chronic inflammatory disease, synovial fibroblasts and T cells play a central role in the evolution of the disease. Recently, the expression of TLR2, -3, -4, and TLR9 in osteoarthritis synovial fibroblasts has been reported (Hu et al, 2014). McKelvey et al (2011) evaluated the expression of five known isoforms of human TLR9, in 15 samples of joint synovial tissue and 15 samples of rheumatoid subcutaneous nodules obtained from patients with RA.…”