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Surface expression of the hRSV nucleoprotein impairs immunological synapse formation with T cells.
Human respiratory syncytial virus (hRSV) is the leading cause of bronchiolitis and pneumonia in young children worldwide. The recurrent hRSV outbreaks and reinfections are the cause of a significant public health burden and associate with an inefficient antiviral immunity, even after disease resolution. Although several mouse- and human cell-based studies have shown that hRSV infection prevents naïve T-cell activation by antigen-presenting cells, the mechanism underlying such inhibition remains unknown. Here, we show that the hRSV nucleoprotein (N) could be at least partially responsible for inhibiting T-cell activation during infection by this virus. Early after infection, the N protein was expressed on the surface of epithelial and dendritic cells, after interacting with trans-Golgi and lysosomal compartments. Further, experiments on supported lipid bilayers loaded with peptide-MHC (pMHC) complexes showed that surface-anchored N protein prevented immunological synapse assembly by naive CD4(+) T cells and, to a lesser extent, by antigen-experienced T-cell blasts. Synapse assembly inhibition was in part due to reduced T-cell receptor (TCR) signaling and pMHC clustering at the T-cell-bilayer interface, suggesting that N protein interferes with pMHC-TCR interactions. Moreover, N protein colocalized with the TCR independently of pMHC, consistent with a possible interaction with TCR complex components. Based on these data, we conclude that hRSV N protein expression at the surface of infected cells inhibits T-cell activation. Our study defines this protein as a major virulence factor that contributes to impairing acquired immunity and enhances susceptibility to reinfection by hRSV.
Tenascin-C: Form versus function.
Tenascin-C is a large, multimodular, extracellular matrix glycoprotein that exhibits a very restricted pattern of expression but an enormously diverse range of functions. Here, we discuss the importance of deciphering the expression pattern of, and effects mediated by, different forms of this molecule in order to fully understand tenascin-C biology. We focus on both post transcriptional and post translational events such as splicing, glycosylation, assembly into a 3D matrix and proteolytic cleavage, highlighting how these modifications are key to defining tenascin-C function.
Tenascin-C: Exploitation and collateral damage in cancer management.
Despite an increasing knowledge about the causes of cancer, this disease is difficult to cure and still causes far too high a death rate. Based on advances in our understanding of disease pathogenesis, novel treatment concepts, including targeting the tumor microenvironment, have been developed and are being combined with established treatment regimens such as surgical removal and radiotherapy. Yet it is obvious that we need additional strategies to prevent tumor relapse and metastasis. Given its exceptional high expression in most cancers with low abundance in normal tissues, tenascin-C appears an ideal candidate for tumor treatment. Here, we will summarize the current applications of targeting tenascin-C as a treatment for different tumors, and highlight the potential of this therapeutic approach.
The extracellular matrix and cancer: regulation of tumor cell biology by tenascin-C
When a plant goes to seed, its seeds are carried in all directions; but they can only live and grow if they fall on congenial soil” - Stephen Paget, 1889 Cancer remains one of the biggest threats to our ever-increasing population; few lives remain untouched by this disease. An estimated 12.7 million new cases were diagnosed worldwide in 2008 and cancer caused an estimated 7.6 million deaths in the same year (IACR, 2008; WHO, 2008). Most of these deaths are a result of cancer that has spread from the original lesion to colonize a new site in the body; indeed metastatic cancers remain the most difficult to treat, with the worst Prognoses. Prompted by the observation that different cancers actually spread to very specific and often very distinct secondary sites, Paget first proposed his ‘seed and soil’ hypothesis to explain this phenomenon over a century ago. His paper highlighted for the first time the importance of the environment or ‘the soil’ in supporting the dissemination of cancer cells, ‘the seed’. Since then an army of researchers around the globe have begun to investigate in greater mechanistic detail precisely how the environment of, not only the metastatic cancer cell, but also the primary cancer cell, dictates disease pathogenesis. Their discoveries have shed light on how the extracellular matrix surrounding and supporting cancer cells is key to driving cancer progression. Here we focus on the progress in our understanding of how one component of the tumor soil, tenascin-C, is responsible for promoting the survival of primary tumor cells. We also review data that reveal a new role for tenascin-C in promoting tumor angiogenesis and enabling the migrating metastatic cancer cell to thrive at secondary tumor sites. Finally, we highlight how this work has opened the door for a variety of new therapeutic interventions that may help to treat cancer.
Raised circulating tenascin-C in rheumatoid arthritis.
INTRODUCTION: The aim of this study was to examine whether circulating levels of the pro-inflammatory glycoprotein tenascin-C (TNC) are elevated in musculoskeletal disorders including rheumatoid arthritis (RA) and to assess in RA whether levels are related to clinical disease status and/or patient response to treatment. METHODS: TNC in serum or plasma was quantified by ELISA. Samples from 4 cohorts of RA patients were examined and compared to normal human subjects and to patients with other inflammatory diseases. RESULTS: Circulating TNC levels were significantly raised in patients with RA, as well as patients with systemic lupus erythematosus, idiopathic inflammatory myositis, psoriatic arthritis and ankylosing spondylitis, whilst patients with Sjogren's syndrome displayed levels similar to healthy controls. The highest levels of TNC were observed in RA patients with late stage disease. In early disease TNC levels correlated positively with ultrasound determined erosion scores. Treatment of early RA patients with infliximab plus methotrexate (MTX) resulted in a transient decrease in circulating TNC over the first year of therapy. In contrast, TNC levels increased over time in RA patients receiving MTX alone. In patients treated with infliximab plus MTX, baseline TNC levels significantly correlated with tender joint counts (TJC) at 18 and 54 weeks after initiation of infliximab therapy. CONCLUSIONS: Raised circulating TNC levels are detected in specific inflammatory diseases. Levels are especially high in RA where they may act as a biomarker of bone erosion and a predictor of the effect of infliximab on RA patient joint pain.
Endogenous activation of adaptive immunity: tenascin-C drives interleukin-17 synthesis in murine arthritic joint disease.
OBJECTIVE: Rheumatoid arthritis is characterized by persistent synovial inflammation and progressive joint destruction, which are mediated by innate and adaptive immune responses. Cytokine blockade successfully treats some patient subsets; however, ∼50% do not respond to this approach. Targeting of pathogenic T lymphocytes is emerging as an effective alternative/complementary therapeutic strategy, yet the factors that control T cell activation in joint disease are not well understood. Tenascin-C is an arthritogenic extracellular matrix glycoprotein that is not expressed in healthy synovium but is elevated in the rheumatoid joint, where high levels are produced by myeloid cells. Among these cells, tenascin-C expression is most highly induced in activated dendritic cells (DCs). The aim of this study was to examine the role of tenascin-C in this cell type. METHODS: We systematically compared the phenotype of DCs isolated from wild-type mice or mice with a targeted deletion of tenascin-C by assessing cell maturation, cytokine synthesis, and T cell polarization. RESULTS: Dendritic cells derived from tenascin-C-null mice exhibited no defects in maturation; induction of the class II major histocompatibility complex and the costimulatory molecules CD40 and CD86 was unimpaired. Dendritic cells that did not express tenascin-C, however, produced lower levels of inflammatory cytokines than did cells from wild-type mice and exhibited specific defects in Th17 cell polarization. Moreover, tenascin-C-null mice displayed ablated levels of interleukin-17 in the joint during experimental arthritis. CONCLUSION: These data demonstrate that tenascin-C is important in DC-mediated polarization of Th17 lymphocytes during inflammation and suggest a key role for this endogenous danger signal in driving adaptive immunity in erosive joint disease.
Plasma and cellular fibronectin: distinct and independent functions during tissue repair.
Fibronectin (FN) is a ubiquitous extracellular matrix (ECM) glycoprotein that plays vital roles during tissue repair. The plasma form of FN circulates in the blood, and upon tissue injury, is incorporated into fibrin clots to exert effects on platelet function and to mediate hemostasis. Cellular FN is then synthesized and assembled by cells as they migrate into the clot to reconstitute damaged tissue. The assembly of FN into a complex three-dimensional matrix during physiological repair plays a key role not only as a structural scaffold, but also as a regulator of cell function during this stage of tissue repair. FN fibrillogenesis is a complex, stepwise process that is strictly regulated by a multitude of factors. During fibrosis, there is excessive deposition of ECM, of which FN is one of the major components. Aberrant FN-matrix assembly is a major contributing factor to the switch from normal tissue repair to misregulated fibrosis. Understanding the mechanisms involved in FN assembly and how these interplay with cellular, fibrotic and immune responses may reveal targets for the future development of therapies to regulate aberrant tissue-repair processes.
DAMPening inflammation by modulating TLR signalling.
Damage-associated molecular patterns (DAMPs) include endogenous intracellular molecules released by activated or necrotic cells and extracellular matrix (ECM) molecules that are upregulated upon injury or degraded following tissue damage. DAMPs are vital danger signals that alert our immune system to tissue damage upon both infectious and sterile insult. DAMP activation of Toll-like receptors (TLRs) induces inflammatory gene expression to mediate tissue repair. However, DAMPs have also been implicated in diseases where excessive inflammation plays a key role in pathogenesis, including rheumatoid arthritis (RA), cancer, and atherosclerosis. TLR activation by DAMPs may initiate positive feedback loops where increasing tissue damage perpetuates pro-inflammatory responses leading to chronic inflammation. Here we explore the current knowledge about distinct signalling cascades resulting from self TLR activation. We also discuss the involvement of endogenous TLR activators in disease and highlight how specifically targeting DAMPs may yield therapies that do not globally suppress the immune system.
The role of tenascin-C in tissue injury and tumorigenesis.
The extracellular matrix molecule tenascin-C is highly expressed during embryonic development, tissue repair and in pathological situations such as chronic inflammation and cancer. Tenascin-C interacts with several other extracellular matrix molecules and cell-surface receptors, thus affecting tissue architecture, tissue resilience and cell responses. Tenascin-C modulates cell migration, proliferation and cellular signaling through induction of pro-inflammatory cytokines and oncogenic signaling molecules amongst other mechanisms. Given the causal role of inflammation in cancer progression, common mechanisms might be controlled by tenascin-C during both events. Drugs targeting the expression or function of tenascin-C or the tenascin-C protein itself are currently being developed and some drugs have already reached advanced clinical trials. This generates hope that increased knowledge about tenascin-C will further improve management of diseases with high tenascin-C expression such as chronic inflammation, heart failure, artheriosclerosis and cancer.
Coregulation of fibronectin signaling and matrix contraction by tenascin-C and syndecan-4.
Syndecan-4 is a ubiquitously expressed heparan sulfate proteoglycan that modulates cell interactions with the extracellular matrix. It is transiently up-regulated during tissue repair by cells that mediate wound healing. Here, we report that syndecan-4 is essential for optimal fibroblast response to the three-dimensional fibrin-fibronectin provisional matrix that is deposited upon tissue injury. Interference with syndecan-4 function inhibits matrix contraction by preventing cell spreading, actin stress fiber formation, and activation of focal adhesion kinase and RhoA mediated-intracellular signaling pathways. Tenascin-C is an extracellular matrix protein that regulates cell response to fibronectin within the provisional matrix. Syndecan-4 is also required for tenascin-C action. Inhibition of syndecan-4 function suppresses tenascin-C activity and overexpression of syndecan-4 circumvents the effects of tenascin-C. In this way, tenascin-C and syndecan-4 work together to control fibroblast morphology and signaling and regulate events such as matrix contraction that are essential for efficient tissue repair.
NG2/HMPG modulation of human articular chondrocyte adhesion to type VI collagen is lost in osteoarthritis.
NG2/human melanoma proteoglycan (HMPG) is a chondroitin sulphate proteoglycan (CSPG), expressed by chondrocytes in fetal and in normal and osteoarthritic (OA) adult articular cartilage. NG2/HMPG is a receptor for extracellular matrix proteins, including type VI collagen, and regulates beta1 integrin binding to fibronectin. This study was undertaken to identify whether NG2/HMPG had similar activities in human articular chondrocytes (HACs). Normal and OA adult HAC adhesion to fibronectin, type II or type VI collagen was assessed using a methylene blue assay. The requirement for integrins, NG2/HMPG, and integrin-associated signalling molecules was investigated using anti-beta1 integrin and anti-HMPG antibodies and pharmacological inhibitors of signalling molecules. The adhesion of normal and OA HACs to fibronectin, type II and type VI collagen was beta1 integrin-dependent. Normal HAC adhesion to type VI collagen was stimulated by anti-HMPG antibodies. This effect was inhibited by pertussis toxin. Anti-HMPG antibodies had no effect on OA chondrocyte adhesion to type VI collagen, or on normal and OA cell adhesion to fibronectin and type II collagen. The results show that NG2/HMPG modulates integrin-mediated interactions of normal HACs with type VI collagen. Loss of this activity may be of importance in the progression of osteoarthritis.
Targeting Toll-like receptors in autoimmunity.
In the past few years there has been an increasing appreciation of the importance of Toll-like receptors (TLRs), not just in immunity, but also in autoimmune diseases. TLRs were first identified as sensors of viral and bacterial pathogens that form an integral part of the innate immune response. It was later discovered that these receptors can also respond to endogenous ligands that are produced as a result of tissue damage. This lead to the hypothesis that TLRs may be key contributors to the pathogenesis of chronic inflammatory conditions. A large body of data supporting the role of TLRs in autoimmunity has emerged from animal models and more data is increasingly being generated from human studies as further tools to examine these receptors have become available. Developing strategies to manipulate TLR function is of great interest in autoimmunity, as well as other diseases that include allergy and cancer. This review explores the evidence that points to a role for TLRs in autoimmunity and highlights some of the potential ways in which modulation of their action may yield clinical benefits.
Advances in tenascin-C biology.
Tenascin-C is an extracellular matrix glycoprotein that is specifically and transiently expressed upon tissue injury. Upon tissue damage, tenascin-C plays a multitude of different roles that mediate both inflammatory and fibrotic processes to enable effective tissue repair. In the last decade, emerging evidence has demonstrated a vital role for tenascin-C in cardiac and arterial injury, tumor angiogenesis and metastasis, as well as in modulating stem cell behavior. Here we highlight the molecular mechanisms by which tenascin-C mediates these effects and discuss the implications of mis-regulated tenascin-C expression in driving disease pathology.