Targeting early changes in the synovial microenvironment: a new class of immunomodulatory therapy?

Aungier, Susan R; Cartwright, Alison; Schwenzer, Anja; Marshall, Jennifer L.; Dyson, Michael R.; Slavny, Peter; Parthiban, Kothai; Karatt-Vellatt, Aneesh; Sahbudin, Ilfita; Culbert, E. J.; Hextall, Patrick; Clanchy, Felix I. L.; Williams, Richard; Marsden, Brian D.; Raza, Karim; Filer, Andrew; Buckley, Christopher D.; McCafferty, John; Midwood, Kim S.

doi:10.1136/annrheumdis-2018-214294

Cited by 22 publications

(23 citation statements)

References 21 publications

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“…Interestingly, tenascin-C can also have immunosuppressive effects through regulating local concentration and activity of the immunosuppressive factor TGF-b (112,125) and through suppression of T-cell activation induced by various stimuli (232,(234)(235)(236)(237). Whether this local regulation of TGF-b by tenascin-C directly affects hepatocyte or cholangiocyte senescence in acute or chronic liver injury is unknown.…”

Section: Ecm Proteins With Both Pro-and Anti-inflammatory Effects On mentioning

confidence: 99%

Immunomodulatory Role of the Extracellular Matrix Within the Liver Disease Microenvironment

et al. 2020

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Chronic liver disease when accompanied by underlying fibrosis, is characterized by an accumulation of extracellular matrix (ECM) proteins and chronic inflammation. Although traditionally considered as a passive and largely architectural structure, the ECM is now being recognized as a source of potent damage-associated molecular pattern (DAMP)s with immune-active peptides and domains. In parallel, the ECM anchors a range of cytokines, chemokines and growth factors, all of which are capable of modulating immune responses. A growing body of evidence shows that ECM proteins themselves are capable of modulating immunity either directly via ligation with immune cell receptors including integrins and TLRs, or indirectly through release of immunoactive molecules such as cytokines which are stored within the ECM structure. Notably, ECM deposition and remodeling during injury and fibrosis can result in release or formation of ECM-DAMPs within the tissue, which can promote local inflammatory immune response and chemotactic immune cell recruitment and inflammation. It is well described that the ECM and immune response are interlinked and mutually participate in driving fibrosis, although their precise interactions in the context of chronic liver disease are poorly understood. This review aims to describe the known pro-/anti-inflammatory and fibrogenic properties of ECM proteins and DAMPs, with particular reference to the immunomodulatory properties of the ECM in the context of chronic liver disease. Finally, we discuss the importance of developing novel biotechnological platforms based on decellularized ECM-scaffolds, which provide opportunities to directly explore liver ECM-immune cell interactions in greater detail.

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Section: Ecm Proteins With Both Pro-and Anti-inflammatory Effects On mentioning

confidence: 99%

Immunomodulatory Role of the Extracellular Matrix Within the Liver Disease Microenvironment

et al. 2020

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“…Tenascin-c is ECM glycoprotein which increased levels were found in the synovial fluid in OA patients [34]. Production of Tnc can also induce inflammatory mediators and promote matrix degradation in OA, and its levels could serve as a biomarker of joint damage and a trigger of further joint degradation [35,36]. In our in vitro system, the level of Tnc was significantly increased in OA chondrocytes compared with control chondrocytes, which was related to Foxo3a expression.…”

Section: Discussionmentioning

confidence: 69%

Foxo3a aggravates inflammation and induces apoptosis in IL-1-treated rabbit chondrocytes via positively regulating tenascin-c

Wang

Qiu-bin

Zhu

et al. 2020

Folia Histochem Cytobiol.

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Introduction. Osteoarthritis (OA) is the most common degenerative disease in middle-aged and elderly individuals that causes joint deformity and limb disability. Accumulating evidence has suggested that the pathogenesis of OA has been related to various mechanisms such as apoptosis, inflammation, oxidative stress and metabolic disorders. The aim of this study is to clarify the role of Foxo3a in the progress of OA in an in vitro model. Materials and methods. The chondrocytes were derived from rabbit, and treated with IL-1b, which was used as an in vitro OA model. The over-expression and down-regulation of Foxo3a were achieved by transfection with overexpression vector or shRNA, respectively. The mRNA level of iNOS in chondrocytes was quantified by qPCR. Tenascin-c (Tnc) production was measured by ELISA and apoptosis-associated proteins were analyzed by Western blotting. The MTT assay was used to assess the viability of chondrocytes. Results. Foxo3a and iNOS expression were upregulated in IL-1b-treated chondrocytes. Foxo3a silencing decreased iNOS expression, and inhibited apoptosis of IL-1b-treated chondrocytes. The production of Tnc was significantly increased in IL-1b-treated chondrocytes and was positively regulated by Foxo3. Importantly, extracellular addition of Tnc abrogated the protective effects of Foxo3a knockdown on IL-1b -treated chondrocytes. Conclusion. The present study indicated that down-regulation of Foxo3a protected IL-1b-treated chondrocytes by decreasing iNOS expression and suppressing chondrocytes' apoptosis via modulating tenascin-c, which could be regarded as a potent therapeutic target for the treatment of OA.

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“…Mapping the active domain within TNC demonstrated a unique structural FBG epitope, essential for binding to and activating TLR4 ( 63 ). Monoclonal antibodies recognizing the FBG domain of TNC inhibited release of TNF-α, IL-6, and IL-8 by RA synovium ( 64 ). Blocking inflammatory signals from the ECM including TNC domains represents a potential novel therapeutic strategy for treating RA that may avoid global immune suppression.…”

Section: Rheumatoid Arthritismentioning

confidence: 99%

Tenascin-C in Osteoarthritis and Rheumatoid Arthritis

2020

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Tenascin-C (TNC) is a large multimodular glycoprotein of the extracellular matrix that consists of four distinct domains. Emerging evidence suggests that TNC may be involved in the pathogenesis of osteoarthritis (OA) and rheumatoid arthritis (RA). In this review, we summarize the current understanding of the role of TNC in cartilage and in synovial biology, across both OA and RA. TNC is expressed in association with the development of articular cartilage; the expression decreases during maturation of chondrocytes and disappears almost completely in adult articular cartilage. TNC expression is increased in diseased cartilage, synovium, and synovial fluid in OA and RA. In addition, elevated circulating TNC levels have been detected in the blood of RA patients. Thus, TNC could be used as a novel biochemical marker for OA and RA, although it has no specificity as a biochemical marker for these joint disorders. In a post-traumatic OA model of aged joints, TNC deficiency was shown to enhance cartilage degeneration. Treatment with TNC domains results in different, domain-specific effects, which are also dose-dependent. For instance, some TNC fragments including the fibrinogen-like globe domain might function as endogenous inducers of synovitis and cartilage matrix degradation through binding with toll-like receptor-4, while full-length TNC promotes cartilage repair and prevents the development of OA without exacerbating synovitis. The TNC peptide TNIIIA2 also prevents cartilage degeneration without causing synovial inflammation. The clinical significance of TNC effects on cartilage and synovium is unclear and understanding the clinical significance of TNC is not straightforward.

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Targeting early changes in the synovial microenvironment: a new class of immunomodulatory therapy?

Cited by 22 publications

References 21 publications

Immunomodulatory Role of the Extracellular Matrix Within the Liver Disease Microenvironment

Immunomodulatory Role of the Extracellular Matrix Within the Liver Disease Microenvironment

Foxo3a aggravates inflammation and induces apoptosis in IL-1-treated rabbit chondrocytes via positively regulating tenascin-c

Tenascin-C in Osteoarthritis and Rheumatoid Arthritis

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