Type I interferons might form the link between Toll-like receptor (TLR) 3/7 and TLR4-mediated synovial inflammation in rheumatoid arthritis (RA)

Abstract

Following preincubation with IFNalpha, IL1beta and IL18, TLR3 and TLR7 mRNA expression was assessed using real-time PCR. Cytokine production after preincubation with IFNalpha and subsequent TLR stimulation was measured. RESULTS: Synovial TLR3/7 expression was co-expressed with IFNalpha, IL1beta and IL18, but not with TNFalpha, IL12 and IL17. Stimulation of TLR3/TLR7 on monocytes, MoDCs or synovial fibroblasts led to secretion of type I IFN but no biologically active IL1beta or IL18 could be detected. Type I IFNalpha increased TLR3/7 mRNA expression whereas IL1beta and IL18 did not. In spite of the fact that the mRNA level of TLR4 remained unchanged, IFNalpha enhanced the response to TLR4 agonists, a phenomenon that was clearly more marked in patients with RA. CONCLUSION: Type I interferons are highly co-expressed with TLR3/TLR7 in RA synovium. They enhance TLR3/TLR7-mediated cytokine production and also TLR4-mediated responses.

Antigen-Presenting Cells and their Fcγ and Toll-Like Receptors: Leading Suspects in Autoimmunity

“…This was previously demonstrated by Boulé et al using murine bone-marrow DCs which produced TNF and BAFF upon the stimulation with chromatin IC [32]. Myeloid DCs, upon the activation with TLR7/8 ligands are able to secrete high levels of IL-12p70 and induce the proliferation of Th1 cells, especially in combination with IFN , IFN or TLR4 ligands [10,38,39]. IL-12p70 is the major cytokine in inducing Th1 responses and thus the production of IFN .…”

“…These findings, together with genetic data concerning IRF5 and STAT4, are indicative of a role for type I IFNs in RA. Supportive of this are the high levels of IFN found in RA synovial tissue and the selective up regulation of type I IFN-response genes in peripheral blood cells from a subgroup of RA patients [10,88]. In addition, it was recently reported that SLE features are common in RA patients given sufficient observation time and that these were associated with increased mortality [89].…”

“…[88] IFN expression in RA synovial tissue. [10] Increased transcription of certain type I IFN regulated genes in peripheral blood cells. [135] Endogenous TLR4ligands in serum.…”

“…Another TLR known for its capability to induce the release of IFNs is TLR4. TLR4 is expressed extracellular and recognizes lipopolysaccharides (LPS) from bacteria and a wide range of endogenous ligands [10]. An important part of its intracellular signaling cascade is shared with TLR3 explaining its capability of triggering IFN production.…”

Targeting DAMP Activation of Toll-Like Receptors: Novel Pathways to Treat Rheumatoid Arthritis?

“…mRNA in RA > OA or non arthritic joints, at synovial lining, sites of attachment and invasion into cartilage or bone, around small vessels and in areas of infiltrating lymphocytes (fibroblasts not macrophages or T cells) yes (Seibl et al, 2003) Protein in RA > OA or healthy joints in synovial lining, sublining and perivascular regions nd Protein in RA blood monocytes, tissue macrophages yes (Iwahashi et al, 2004;Huang et al, 2007) Protein in fibroblasts from RA > OA joints > healthy skin yes TLR3 mRNA and protein in RA > OA or healthy synovium, in fibroblasts of the synovial lining and sublining, and in the perivascular areas yes (Brentano et al, 2005;Roelofs et al, 2005) Protein in fibroblasts from early RA > OA or healthy synovium yes (Ospelt et al, 2008) TLR4 mRNA in RA synovial tissue, protein in DCs and macrophages but not T cells or fibroblasts from RA joint yes ) (Tamaki et al, 2011) (Huang et al, 2007) Protein in synovial tissue from RA > OA > healthy joints, in early and longstanding RA yes ) (Ospelt et al, 2008) Protein in RA synovial fibroblasts yes Wu et al, 2010) TLR5 Protein in DCs> macrophages > fibroblasts from RA joint nd (Tamaki et al, 2011) TLR6 Protein in DCs> macrophages > fibroblasts from RA joint nd (Tamaki et al, 2011) TLR7 Protein in RA synovium > OA or healthy joints yes (Roelofs et al, 2005;Roelofs et al, 2009) TLR9 Protein in DCs> macrophages > fibroblasts from RA joint nd (Tamaki et al, 2011) nd = not determined F= function = the ability of the TLR to respond to its cognate ligand in each cell/tissue type Further studies using ex vivo human disease models have provided evidence of a functional role for TLRs in driving inflammation in RA. Adenoviral over expression of dominant negative Myd88, an adaptor molecule required for signalling by all TLRs except TLR3, inhibited cytokine synthesis in RA synovial cells .…”