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Date & time Aug 13
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like receptor 4 that is essential for maintaining inflammation in arthritic joint disease

Tenascin C is an endogenous activator of Toll like receptor 4 that is essential for maintaining inflammation in arthritic joint diseaseKim Midwood1,Anna M Piccinini1,AbstractAlthough there have been major advances in the treatment of rheumatoid arthritis with the advent of biological agents, the mechanisms that drive cytokine production and sustain disease chronicity remain unknown. Tenascin C (encoded by Tnc) is an extracellular matrix glycoprotein specifically expressed at areas of inflammation and tissue damage in inflamed rheumatoid joints. Here we show that mice that do not express tenascin C show rapid resolution of acute joint inflammation and are protected from erosive arthritis. Intra articular injection of tenascin C promotes joint inflammation in vivo in mice,perpetual date rolex replica, and addition of exogenous tenascin C induces cytokine synthesis in explant cultures from inflamed synovia of individuals with rheumatoid arthritis. Moreover, in human macrophages and fibroblasts from synovia of individuals with rheumatoid arthritis, tenascin C induces synthesis of proinflammatory cytokines via activation of Toll like receptor 4 (TLR4). Thus, we have identified tenascin C as a novel endogenous activator of TLR4 mediated immunity that mediates persistent synovial inflammation and tissue destruction in arthritic joint disease.

IntroductionRheumatoid arthritis is characterized by synovial inflammation and destruction of joint cartilage and bone mediated by persistent synthesis of proinflammatory cytokines and matrix metalloproteinases. Biological compounds that suppress the synthesis of key inflammatory cytokines, including tumor necrosis factor (TNF ) and interleukin 6 (IL 6), are successful at treating rheumatoid arthritis in the short term. However, repeated treatments are required, rendering this an expensive therapeutic approach that does not lead to long term remission. Total systemic suppression of cytokine function is not without inherent problems, such as increased infectious risk. Thus,imitation rolex oyster date, despite advances in care, there remains an unmet need for an economical mode of treatment that is efficacious over the long term1, 2. However, a major obstacle lies in the fact that the mechanisms that underpin disease chronicity remain unclear, and the factor(s) that drive the prolonged expression of inflammatory and destructive mediators are unknown.

TLRs have a key role in driving inflammation, and blockade of TLR function may yield considerable clinical benefit3, 4. This receptor family mediates host defense against infection and injury by recognizing pathogen and damage associated molecular patterns (PAMPs and DAMPs)5. DAMPs are endogenous proinflammatory molecules generated upon tissue injury and include intracellular molecules released from necrotic cells, extracellular matrix fragments or extracellular matrix molecules upregulated upon injury6, 7. Upon activation, TLRs promote innate and adaptive immune responses, including induction of proinflammatory cytokines and matrix metalloproteinases8. TLRs are highly expressed in synovial tissue from individuals with rheumatoid arthritis9, 10, 11, 12, and mice with targeted deletions or loss of function mutations in Tlr4 are protected from experimental arthritis13, 14. Furthermore, inhibitors of TLR4 have reduced destructive arthritis in mice15 and improved symptoms in patients with moderate to severe rheumatoid arthritis in a preliminary phase 1 trial16.

However, it is unclear which TLR ligand(s) are involved in disease pathogenesis. Tenascin C is an extracellular matrix glycoprotein associated with tissue injury and repair. It is not normally expressed in most adult tissues but is specifically and transiently upregulated during acute inflammation and persistently expressed in chronic inflammation17. Little tenascin C is expressed in normal human joints, but expression is increased in synovia18, 19, 20, synovial fluid21, 22 and cartilage20, 21 from individuals with rheumatoid arthritis. It is a hexameric protein of 1.5 million Da that comprises an assembly domain, epidermal growth factor repeats (EGF L), fibronectin type III repeats (TNIII) and a fibrinogen like globe (FBG)23. The elevated amounts of tenascin C in rheumatoid arthritis and the homology of tenascin C domains to other known DAMPs prompted us to examine whether this molecule is a TLR ligand that contributes to the progression of inflammatory joint disease.

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ResultsZymosan induced inflammation is not sustained in Tnc / miceWe used zymosan to induce acute synovitis in mice. Wild type mice showed rapid paw swelling that reached maximal diameter by 24 h and that was maintained for a further 24 h (Fig. 1a). After 2 d, the paw diameter decreased, but paws remained swollen at 4 d (Fig. 1a). There was no significant difference in the paw swelling of Tnc / mice compared to wild type mice 24 h after injection (Fig. 1a). However, swelling subsided faster than in wild type mice; paw diameter was significantly lower at 2 d and had declined to near basal levels by 4 d (Fig. 1a). By 4 d, the paws of wild type mice were still visibly swollen and red, whereas the paws of Tnc / mice resembled noninjected paws (Supplementary Fig. 1).

Figure 1: Accelerated resolution of acute inflammation in Tnc / mice.

(a) Paw swelling in wild type (+/+) and Tnc / ( / ) mice over time after injection of zymosan. (n = 24 mice per genotype). P b Representative sections of the ankle joints from wild type (b,c) and Tnc / (d,e) mice 4 d after zymosan injection, stained with H (b,d) and safranin O (c,replica rolex date just,e). Boxes highlight the joint synovium (s) and cartilage proteoglycan (cp). Scale bar, 250 m. (f) Quantification of joint inflammation and chondrocyte death in knee joints 4 d after injection with zymosan from wild type mice and Tnc / mice. (n = 24 mice per genotype). P P

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Histologically, synovia of wild type mice were substantially inflamed at 4 d, showing cellular infiltration and cartilage proteoglycan loss (Fig. 1b,c). In contrast, Tnc / mice showed no synovitis, cellular infiltrate or cartilage proteoglycan loss (Fig. 1d,e). There was little cellular exudate in either wild type or Tnc / mice; however, cellular infiltration was significantly lower in Tnc / mice (Fig. 1f). No erosion of cartilage or bone occurred in mice of either genotype (data not shown); however, chondrocyte death occurred in wild type but not Tnc / mice (Fig. 1f). Tenascin C expression was elevated in the joints of wild type mice 24 h after injection, and expression increased over time up to 4 d (Supplementary Fig. 2a). Induction of tenascin C expression was specific to the zymosan injected joint and was not observed in the contralateral, noninjected joint of the same mouse (data not shown). Thus, tenascin C expression seems to promote the maintenance of acute inflammation.

Tnc / mice are protected from joint destruction

To determine whether tenascin C contributes to more destructive inflammatory joint disease, we induced erosive arthritis by immunization and intra articular injection with methylated BSA (mBSA) (Fig. 2), a model that induces pathological changes similar to human rheumatoid arthritis24. Cell infiltration and synovial thickening was apparent by 24 h in mice of both genotypes (Fig. 2c compared to sham injected (Fig. 2a,b,g) or noninjected (data not shown) mice.

Figure 2: Synovial inflammation is induced in Tnc / mice upon injection of antigen.

(a,b) Representative sections of the knee joints of sham injected wild type mice. (c Representative sections of the knee joints of wild type (c,d) or Tnc / (e,f) mice 24 h after intra articular injection of mBSA. Inflammatory cell infiltration is indicated in the capsule (cap), meniscus (M) and the joint space (J) of both wild type and Tnc / mice. (g Higher magnification images show the synovium of sham injected wild type mice (g), wild type mice injected with mBSA (h) or Tnc / mice injected with mBSA (i). 'S' indicates the healthy synovium of sham injected mice that is no more than 1 cells thick along the entire bone surface, and 'ST' highlights the synovia of wild type and Tnc / mice, which are both considerably thickened. Sections are stained with H (a, c, e,imitation rolex lady day date, g and safranin O (b,d,f). Scale bars, 250 m (a and 50 m (g n = 5 mice per genotype.
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