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Collagen Receptors (collagen + receptor)
Selected AbstractsIncreased expression of collagen receptors: ,1,1 and ,2,1 integrins on blood eosinophils in bronchial asthmaCLINICAL & EXPERIMENTAL ALLERGY, Issue 9 2006S. Bazan-Socha Summary Background Eosinophils are one of the major effector cells in bronchial asthma. Their infiltration of airways correlates with the asthma severity. Recruitment and activation of eosinophils are partially mediated by integrins ,4,1 and ,4,7. Collagens type I and IV constitute important components of extracellular matrix and vascular basement membrane, respectively. Therefore, collagen-binding integrins (,1,1 and ,2,1) may also play a role in eosinophil lung infiltration. Objective To evaluate the possible presence of ,1,1 and ,2,1 integrins on peripheral blood eosinophils from asthmatic subjects. Methods Collagen receptors were studied on eosinophils separated by immunomagnetic CD16-negative method from healthy donors (n=13) and patients with moderate persistent atopic bronchial asthma (n=15). Surface receptor identification was performed by flow cytometry and cell adhesion assay. Results Eosinophils isolated from the patients showed increased expression of both ,1,1 and ,2,1 integrins as compared with healthy controls. Moreover, adhesive function of eosinophils to collagen type IV was inhibited by snake venom disintegrins: viperistatin and obtustatin. These disintegrins contain KTS active motif and are specific inhibitors of ,1,1 integrin. Conclusion We demonstrated for the first time that collagen receptors: ,1,1 and ,2,1 integrins are overexpressed on the surface of peripheral blood eosinophils of asthmatic subjects. Further studies may reveal potential application of KTS-disintegrins or their structural analogs for therapy of bronchial asthma. [source] Alpha2beta1 integrin is the major collagen-binding integrin expressed on human Th17 cellsEUROPEAN JOURNAL OF IMMUNOLOGY, Issue 10 2010Marc Boisvert Abstract Growing evidence indicates that collagen-binding integrins are important costimulatory molecules of effector T cells. In this study, we demonstrate that the major collagen-binding integrin expressed by human Th17 cells is alpha2beta1 (,2,1) or VLA-2, also known as the receptor for collagen I on T cells. Our results show that human naïve CD4+ T cells cultured under Th17 polarization conditions preferentially upregulate ,2,1 integrin rather than ,1,1 integrin, which is the receptor for collagen IV on T cells. Double staining analysis for integrin receptors and intracellular IL-17 showed that ,2 integrin but not ,1 integrin is associated with Th17 cells. Cell adhesion experiments demonstrated that Th17 cells attach to collagen I and collagen II using ,2,1 integrin but did not attach to collagen IV. Functional studies revealed that collagens I and II but not collagen IV costimulate the production of IL-17A, IL-17F and IFN-, by human Th17 cells activated with anti-CD3. These results identify ,2,1 integrin as the major collagen receptor expressed on human Th17 cells and suggest that it can be an important costimulatory molecule of Th17 cell responses. [source] Regulation of chondrocyte differentiation by the actin cytoskeleton and adhesive interactionsJOURNAL OF CELLULAR PHYSIOLOGY, Issue 1 2007Anita Woods Chondrocyte differentiation is a multi-step process characterized by successive changes in cell morphology and gene expression. In addition to tight regulation by numerous soluble factors, these processes are controlled by adhesive events. During the early phase of the chondrocyte life cycle, cell,cell adhesion through molecules such as N-cadherin and neural cell adhesion molecule (N-CAM) is required for differentiation of mesenchymal precursor cells to chondrocytes. At later stages, for example in growth plate chondrocytes, adhesion signaling from extracellular matrix (ECM) proteins through integrins and other ECM receptors such as the discoidin domain receptor (DDR) 2 (a collagen receptor) and Annexin V is necessary for normal chondrocyte proliferation and hypertrophy. Cell,matrix interactions are also important for chondrogenesis, for example through the activity of CD44, a receptor for Hyaluronan and collagens. The roles of several signaling molecules involved in adhesive signaling, such as integrin-linked kinase (ILK) and Rho GTPases, during chondrocyte differentiation are beginning to be understood, and the actin cytoskeleton has been identified as a common target of these adhesive pathways. Complete elucidation of the pathways connecting adhesion receptors to downstream effectors and the mechanisms integrating adhesion signaling with growth factor- and hormone-induced pathways is required for a better understanding of physiological and pathological skeletal development. J. Cell. Physiol. 213: 1,8, 2007. © 2007 Wiley-Liss, Inc. [source] An acquired inhibitor to the GPVI platelet collagen receptor in a patient with lupus nephritisJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 9 2009P. NURDEN Summary.,Background: GPVI is a major platelet collagen signaling receptor. In rare cases of immune thrombocytopenic purpura (ITP), autoantibodies to GPVI result in receptor shedding. Objectives: To investigate a possible pathogenic role of plasma anti-GPVI antibody located in a woman with lupus nephritis. Methods: Measured were (i) platelet aggregation to collagen and convulxin, (ii) platelet GPVI expression (flow cytometry and western blotting), (iii) plasma soluble GPVI (sGPVI, dual antibody ELISA), and (iv) plasma anti-GPVI antibody (ELISA using recombinant sGPVI). Results: In 2006 and early 2007, the patient had a normal platelet count but a virtual absence of platelet aggregation to collagen and convulxin. Her platelets responded normally to other agonists including cross-linking ITAM-dependent Fc,RIIA by monoclonal antibody, IV.3. Flow cytometry and western blotting showed a platelet deficiency of GPVI. Plasma sGPVI levels were undetectable whereas ELISA confirmed the presence of anti-GPVI antibody. Sequencing revealed a normal GPVI cDNA structure. The patient's plasma and the isolated IgG3 fraction activated and induced GPVI shedding from normal platelets. A deteriorating clinical condition led to increasingly strict immunosuppressive therapy. This was globally associated with a fall in plasma anti-GPVI titres, the restoration of platelet GPVI and the convulxin response, and the loss of her nephrotic syndrome. Conclusions: Our results show that this patient acquired a potent anti-GPVI IgG3 antibody with loss of GPVI and collagen-related platelet function. Further studies are required to determine whether anti-GPVI antibodies occur in other lupus patients with nephritis. [source] Collagen promotes sustained glycoprotein VI signaling in platelets and cell linesJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 11 2007M. G. TOMLINSON Summary. Background:,Glycoprotein (GP)VI is the major signaling receptor for collagen on platelets and signals via the associated FcR,-chain, which has an immunoreceptor tyrosine-containing activation motif (ITAM). Objective:,To determine why GPVI,FcR, signals poorly, or not at all, in response to collagen in hematopoietic cell lines, despite robust responses to the GPVI-reactive snake venom toxin convulxin. Methods and results:,Using a nuclear factor of activated T-cells (NFAT) transcriptional reporter assay, a sensitive readout for sustained ITAM signaling, we demonstrate collagen-induced GPVI,FcR, signaling in hematopoietic cell lines. This is accompanied by relatively weak but sustained protein tyrosine phosphorylation, in contrast to the stronger but transient response to convulxin. Sustained signaling by collagen is also observed in platelets and is necessary for the maintenance of spreading on collagen. Finally, in cell lines, the inhibitory collagen receptor leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1), which is not expressed on platelets but is present on most hematopoietic cells, inhibits GPVI responses to collagen but not convulxin. Conclusion:,The inability of previous studies to readily detect GPVI collagen signaling in cell lines is probably because of the weak but sustained nature of the signal and the presence of the inhibitory collagen receptor LAIR-1. In platelets, we propose that GPVI,FcR, has evolved to transmit sustained signals in order to maintain spreading over several hours, as well as facilitating rapid activation through release of feedback agonists and integrin activation. The establishment of a cell line NFAT assay will facilitate the molecular dissection of GPVI signaling and the identification of GPVI antagonists in drug discovery. [source] Fps/Fes and Fer non-receptor protein-tyrosine kinases regulate collagen- and ADP-induced platelet aggregationJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 5 2003Y. A. Senis Summary., Fps/Fes and Fer proto-oncoproteins are structurally related non-receptor protein-tyrosine kinases implicated in signaling downstream from cytokines, growth factors and immune receptors. We show that Fps/Fes and Fer are expressed in human and mouse platelets, and are activated following stimulation with collagen and collagen-related peptide (CRP), suggesting a role in GPVI receptor signaling. Fer was also activated following stimulation with thrombin and a protease-activated receptor4 (PAR4)-activating peptide, suggesting a role in signaling downstream from the G protein-coupled PAR4. There were no detectable perturbations in CRP-induced activation of Syk, PLC,2, cortactin, Erk, Jnk, Akt or p38 in platelets from mice lacking Fps/Fes, Fer, or both kinases. Platelets lacking Fps/Fes, from a targeted fps/fes null strain of mice, showed increased rates and amplitudes of collagen-induced aggregation, relative to wild-type platelets. P-Selectin expression was also elevated on the surface of Fps/Fes-null platelets in response to CRP. Fer-deficient platelets, from mice targeted with a kinase-inactivating mutation, disaggregated more rapidly than wild-type platelets in response to ADP. This report provides the first evidence that Fps/Fes and Fer are expressed in platelets and become activated downstream from the GPVI collagen receptor, and that Fer is activated downstream from a G-protein coupled receptor. Furthermore, using targeted mouse models we show that deficiency in Fps/Fes or Fer resulted in disregulated platelet aggregation and disaggregation, demonstrating a role for these kinases in regulating platelet functions. [source] Nitric oxide specifically inhibits integrin-mediated platelet adhesion and spreading on collagenJOURNAL OF THROMBOSIS AND HAEMOSTASIS, Issue 12 2008W. ROBERTS Summary.,Background:,Nitric oxide (NO) inhibits platelet adhesion to collagen, although the precise molecular mechanisms underlying this process are unclear. Objectives:,Collagen-mediated adhesion is a multifaceted event requiring multiple receptors and platelet-derived soluble agonists. We investigated the influence of NO on these processes. Results:,S-nitrosoglutathione (GSNO) induced a concentration-dependent inhibition of platelet adhesion to immobilized collagen. Maximal adhesion to collagen required platelet-derived ADP and TxA2. GSNO-mediated inhibition was lost in the presence of apyrase and indomethacin, suggesting that NO reduced the availability of, or signaling by, ADP and TxA2. Exogenous ADP, but not the TxA2 analogue U46619, reversed the inhibitory actions of GSNO on adhesion. Under adhesive conditions NO inhibited dense granule secretion but did not influence TxA2 generation. These data indicated that NO may block signaling by TxA2 required for dense granule secretion, thereby reducing the availability of ADP. Indeed, we found TxA2 -mediated activation of PKC was required to drive dense granule secretion, a pathway that was inhibited by NO. Because our data demonstrated that NO only inhibited the activation-dependent component of adhesion, we investigated the effects of NO on individual collagen receptors. GSNO inhibited platelet adhesion and spreading on ,2,1 specific peptide ligand GFOGER. In contrast, GSNO did not inhibit GPVI-mediated adhesion to collagen, or adhesion to the GPVI specific ligand, collagen related peptide (CRP). Conclusions:,NO targets activation-dependent adhesion mediated by ,2,1, possibly by reducing bioavailability of platelet-derived ADP, but has no effect on activation-independent adhesion mediated by GPVI. Thus, NO regulates platelet spreading and stable adhesion to collagen. [source] Interactions of Platelets with Subendothelium and EndotheliumMICROCIRCULATION, Issue 3 2005JUNMEI CHEN PhD ABSTRACT In this review, the authors summarize how platelets interact with subendothelium when the vessel wall is damaged or with intact endothelium in the inflammatory state. When subendothelium is exposed to rapidly flowing blood upon vessel damage, platelets adhere rapidly to the exposed surface, decelerate, and aggregate to arrest bleeding. Under high shear stress, such as is found in the microcirculation, the interaction between subendothelial von Willebrand factor (VWF) and its platelet receptor, glycoprotein (GP) Ib-IX-V, is required to slow down platelets and allow the platelet collagen receptors ,2,1 and GP VI to bind to collagen. GP VI and ,2,1 play important roles to activate platelets in the early stage and work with GP Ib-IX-V to fully activate platelets to form thrombi. GP Ib-IX-V and GP VI employ similar signaling pathways for platelet activation and the signals from both receptors are down-modulated by PECAM-1 (platelet,endothelial,cell adhesion molecule 1) to prevent unnecessary platelet activation under high shear. During inflammatory states, intact endothelial cells release VWF and P-selectin from their Weibel-Palade bodies. Both molecules are ligands for GP Ib-IX-V. The newly released VWF is larger and stickier than the form normally found in plasma and binds platelets spontaneously. Normally, VWF is processed by proteolysis by the plasma metalloprotease ADAMTS-13. Failure of this processing results in the microvascular thrombotic disorder thrombotic thrombocytopenic purpura. In this review, the authors also use available crystal structures of platelet receptors and ligands to explain the details of their interactions. [source] Type II collagen levels correlate with mineralization by articular cartilage vesiclesARTHRITIS & RHEUMATISM, Issue 9 2009Brian Jubeck Objective Pathologic mineralization is common in osteoarthritic (OA) cartilage and may be mediated by extracellular organelles known as articular cartilage vesicles (ACVs). Paradoxically, ACVs isolated from OA human cartilage mineralize poorly in vitro compared with those isolated from normal porcine cartilage. We recently showed that collagens regulate ACV mineralization. We sought to determine differences between collagens and collagen receptors on human and porcine ACVs as a potential explanation of their different mineralization behaviors. Methods ACVs were enzymatically released from old and young human and porcine hyaline articular cartilage. Western blotting was used to determine the presence of types I, II, VI, and X collagen and various collagen receptors on ACVs. Type II collagen was quantified by enzyme-linked immunosorbent assay. Biomineralization was assessed by measuring the uptake of 45Ca by isolated ACVs in agarose gels and by ACVs in situ in freeze-thawed cartilage. Results As previously shown, isolated human ACVs mineralized poorly in response to ATP compared with porcine ACVs, but human and porcine ACVs mineralized similarly in situ in freeze-thawed cartilage. Type II collagen levels were 100-fold higher in isolated human ACVs than in porcine ACVs. Type II collagen in human ACVs was of high molecular weight. Transglutaminase-crosslinked type II collagen showed increased resistance to collagenase, suggesting a possible explanation for residual collagen on human ACVs. Expression of other collagens and collagen receptors was similar on human and porcine ACVs. Conclusion Higher levels of type II collagen in human ACV preparations, perhaps mediated by increased transglutaminase crosslinking, may contribute to the decreased mineralization observed in isolated human ACVs in vitro. [source] Increased expression of collagen receptors: ,1,1 and ,2,1 integrins on blood eosinophils in bronchial asthmaCLINICAL & EXPERIMENTAL ALLERGY, Issue 9 2006S. Bazan-Socha Summary Background Eosinophils are one of the major effector cells in bronchial asthma. Their infiltration of airways correlates with the asthma severity. Recruitment and activation of eosinophils are partially mediated by integrins ,4,1 and ,4,7. Collagens type I and IV constitute important components of extracellular matrix and vascular basement membrane, respectively. Therefore, collagen-binding integrins (,1,1 and ,2,1) may also play a role in eosinophil lung infiltration. Objective To evaluate the possible presence of ,1,1 and ,2,1 integrins on peripheral blood eosinophils from asthmatic subjects. Methods Collagen receptors were studied on eosinophils separated by immunomagnetic CD16-negative method from healthy donors (n=13) and patients with moderate persistent atopic bronchial asthma (n=15). Surface receptor identification was performed by flow cytometry and cell adhesion assay. Results Eosinophils isolated from the patients showed increased expression of both ,1,1 and ,2,1 integrins as compared with healthy controls. Moreover, adhesive function of eosinophils to collagen type IV was inhibited by snake venom disintegrins: viperistatin and obtustatin. These disintegrins contain KTS active motif and are specific inhibitors of ,1,1 integrin. Conclusion We demonstrated for the first time that collagen receptors: ,1,1 and ,2,1 integrins are overexpressed on the surface of peripheral blood eosinophils of asthmatic subjects. Further studies may reveal potential application of KTS-disintegrins or their structural analogs for therapy of bronchial asthma. [source] |