Local Interleukin-1-Driven Joint Pathology Is Dependent on Toll-Like Receptor 4 Activation

Abstract

Toll-like receptors (TLRs) may contribute to the pathogenesis of chronic inflammatory destructive diseases through the recognition of endogenous ligands produced on either inflammation or degeneration of the extracellular matrix. The presence of endogenous TLR agonists has been reported in rheumatoid joints. In the present study, we investigated the significance of TLR2 and TLR4 activation by locallyproduced endogenous ligands in the severity of joint inflammation and destruction. Local joint pathology independent of systemic immune activation was induced by overexpression of interleukin (IL)-1 and TNF in naive joints using adenoviral gene transfer. Here, we report that at certain doses, IL-1-induced local joint inflammation, cartilage proteoglycan depletion, and bone erosion are dependent on TLR4 activation, whereas TLR2 activation is not significantly involved. In comparison, tumor necrosis factor ␣-driven joint pathology seemed to be less dependent on TLR2 and TLR4. The severity of IL-1-induced bone erosion and irreversible cartilage destruction was markedly reduced in TLR4 ؊/؊ mice, even though the degree of inflammation was similar, suggesting uncoupled processes. Furthermore, the expression of cathepsin K, a marker for osteoclast activity, induced by IL-1␤ was dependent on TLR4. Overexpression of IL-1␤ in the joint as well as ex vivo IL-1 stimulation of patellae provoked the release of endogenous TLR4 agonists capable of inducing TLR4-mediated cytokine production. These data emphasize the potential relevance of TLR4 activation in rheumatoid arthritis , particularly with respect to IL-1-mediated joint pathology.

Inhibition of HDAC Activity by ITF2357 Ameliorates Joint Inflammation and Prevents Cartilage and Bone Destruction in Experimental Arthritis

“…IL-1β appears to be the most potent cytokine studied to date with respect to chondrocyte PG-synthesis. Overexpression of IL-1β results in irreversible cartilage destruction (27). It is likely that the same modulation of IL-1 by HDACi as seen in other models of inflammation accounts for the reduced inhibition of chondrocyte PG-synthesis seen here, and hence in a protective effect against cartilage catabolism during arthritis.…”

“…Of interest, in the beginning of the cytokine era, IL-1 was also named by Jeremy Saklatvala "catabolin," referring to its potent cartilage destructive properties (26). Thereafter, it was demonstrated that IL-1 contributes to joint inflammation and severe cartilage destruction (27). IL-1 exerts potent arthritogenic activity when injected directly into murine knee joints, whereas TNFα induces joint swelling and influx of cells into the joint space (28).…”

Impact of IL-1 signalling on experimental uveitis and arthritis

“…TLR4 is required for the spontaneous onset of murine arthritis in the absence of IL-1Ra, and exposure to a small dose of endotoxin (LPS) has long-lasting effects on arthritis severity,28 30 31 suggesting a gene–environment interaction in the pathogenesis. The data in figure 1 show that a low-dose exposure to LPS at 7 weeks of age significantly exacerbates the inflammation present several weeks later in the ankle and to a lesser extent in the knee.…”

Periodontal Pathogens Directly Promote Autoimmune Experimental Arthritis by Inducing a TLR2- and IL-1–Driven Th17 Response

“…RNA isolation, quantitative PCR analysis, and GAPDH and cathepsin K primer sequences were as described before (23).…”