Abstract
IntroductionToll-like receptor (TLR)4 promotes joint inflammation in mice. Despite that several studies report a functional link between TLR4 and interleukin-(IL-)1β in arthritis, TLR4-mediated regulation of the complicated cytokine network in arthritis is poorly understood. To address this, we investigated the mechanisms by which TLR4 regulates the cytokine network in antibody-induced arthritis.MethodsTo induce arthritis, we injected mice with K/BxN serum. TLR4-mediated pathogenesis in antibody-induced arthritis was explored by measuring joint inflammation, cytokine levels and histological alteration.ResultsCompared to wild type (WT) mice, TLR4-/- mice showed attenuated arthritis and low interferon (IFN)-γ, IL-12p35 and IL-1β transcript levels in the joints, but high transforming growth factor (TGF)-β expression. Injection of lipopolysaccharide (LPS) enhanced arthritis and exaggerated joint cytokine alterations in WT, but not TLR4-/- or IL-12p35-/- mice. Moreover, STAT4 phosphorylation in joint cells and intracellular IL-12p35 expression in macrophages, mast cells and Gr-1+ cells were detected in WT mice with arthritis and enhanced by LPS injection. Therefore, IL-12p35 appears to act downstream of TLR4 in antibody-induced arthritis. TLR4-mediated IL-12 production enhanced IFN-γ and IL-1β production via T-bet and pro-IL-1β production. Recombinant IL-12, IFN-γ and IL-1β administration restored arthritis, but reduced joint TGF-β levels in TLR4-/- mice. Moreover, a TGF-β blockade restored arthritis in TLR4-/- mice. Adoptive transfer of TLR4-deficient macrophages and mast cells minimally altered joint inflammation and cytokine levels in macrophage- and mast cell-depleted WT mice, respectively, whereas transfer of WT macrophages or mast cells restored joint inflammation and cytokine expression. Gr-1+ cell-depleted splenocytes partially restored arthritis in TLR4-/- mice.ConclusionTLR4-mediated IL-12 production by joint macrophages, mast cells and Gr-1+ cells enhances IFN-γ and IL-1β production, which suppresses TGF-β production, thereby promoting antibody-induced arthritis.
Highlights
Toll-like receptor (TLR)4 promotes joint inflammation in mice
Consistent with the TLR4 expression pattern in the joints, expression of endogenous TLR4 ligands, such as HSP60, HMGB1 and fibronectin, were increased in the joints of wild type (WT) mice at Day 7 after K/BxN serum transfer (Figure 1B). These findings suggest that TLR4 expression in the joints may be involved in the pathogenesis of antibody-induced arthritis
To investigate LPSmediated TLR4 signaling in antibody-induced arthritis, we injected WT mice with an amount of K/BxN serum that resulted in sub-maximal joint swelling because LPS injection did not alter full-blown arthritis in WT mice (Figure 1C, E)
Summary
Toll-like receptor (TLR) promotes joint inflammation in mice. We investigated the mechanisms by which TLR4 regulates the cytokine network in antibody-induced arthritis. TLR4 attenuated joint inflammation in IL-1 receptor antagonist-knockout (IL-1rn-/-) and collagen-induced arthritis (CIA) mouse models, depending on MyD88 [7]. In patients with RA, TLR4 expression is increased in synovial tissues at both early and late stages compared to those with osteoarthritis [9] These findings suggest that TLR4mediated signals promote joint inflammation in murine models and RA patients. With respect to the TLR4mediated pathogenesis of RA, TLR4 inhibition reduces the severity of CIA and joint IL-1 expression [10], while IL-1-induced joint inflammation depends on TLR4 activation [11], suggesting that IL-1 signaling is associated with TLR4-mediated immune regulation in the joints. The mechanism by which TLR4 regulates autoimmune joint inflammation via IL-1b signals is unknown
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