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      Wnt5a, TLR2 and TLR4 are elevated in advanced human atherosclerotic lesions

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          Abstract

          Objective and design

          Atherosclerosis (ATH) is a chronic inflammatory disease that involves cascades of signaling events mediated by various effector proteins. Here we sought to determine if the expression of Wnt5a, a secreted glycoprotein, is altered in discrete regions of the arterial plaque.

          Methods

          Atherosclerotic plaque tissues from 14 human subjects undergoing elective carotid endarterectomy were used in this study. Immunohistochemistry and laser capture microdissection combined with quantitative real-time PCR were used to determine the expression of Wnt5a and Toll-like receptors (TLRs) in different sections of the arterial lesions. Atherosclerotic serum samples ( n = 30) and serum from healthy subjects ( n = 16) were quantified for Wnt5a using an enzyme-linked immunosorbent assay (ELISA).

          Results

          The data analysis revealed that Wnt5a transcripts and protein were elevated in advanced arterial lesions relative to less advanced arterial lesions; that Wnt5a expression correlated with the presence of TLR4 and TLR2 transcripts; and that the average amount of Wnt5a protein present in atherosclerotic patient serum was significantly higher compared to healthy controls.

          Conclusions

          This study is the first to provide evidence that the expression of Wnt5a increases as the disease progresses to a more advanced stage, and that this expression is coincident with that of TLR2 and TLR4. In addition, we found that the average Wnt5a levels in the serum of atherosclerotic patients are elevated relative to healthy controls, which is consistent with the hypothesis that Wnt5a plays a role in ATH.

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          Most cited references 28

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          The Wnt signaling pathway in development and disease.

          Tight control of cell-cell communication is essential for the generation of a normally patterned embryo. A critical mediator of key cell-cell signaling events during embryogenesis is the highly conserved Wnt family of secreted proteins. Recent biochemical and genetic analyses have greatly enriched our understanding of how Wnts signal, and the list of canonical Wnt signaling components has exploded. The data reveal that multiple extracellular, cytoplasmic, and nuclear regulators intricately modulate Wnt signaling levels. In addition, receptor-ligand specificity and feedback loops help to determine Wnt signaling outputs. Wnts are required for adult tissue maintenance, and perturbations in Wnt signaling promote both human degenerative diseases and cancer. The next few years are likely to see novel therapeutic reagents aimed at controlling Wnt signaling in order to alleviate these conditions.
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            Heart disease and stroke statistics--2012 update: a report from the American Heart Association.

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              Toll-like receptors in innate immunity.

              Functional characterization of Toll-like receptors (TLRs) has established that innate immunity is a skillful system that detects invasion of microbial pathogens. Recognition of microbial components by TLRs initiates signal transduction pathways, which triggers expression of genes. These gene products control innate immune responses and further instruct development of antigen-specific acquired immunity. TLR signaling pathways are finely regulated by TIR domain-containing adaptors, such as MyD88, TIRAP/Mal, TRIF and TRAM. Differential utilization of these TIR domain-containing adaptors provides specificity of individual TLR-mediated signaling pathways. Several mechanisms have been elucidated that negatively control TLR signaling pathways, and thereby prevent overactivation of innate immunity leading to fatal immune disorders. The involvement of TLR-mediated pathways in autoimmune and inflammatory diseases has been proposed. Thus, TLR-mediated activation of innate immunity controls not only host defense against pathogens but also immune disorders.
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                Author and article information

                Contributors
                malgor@ohio.edu
                Journal
                Inflamm Res
                Inflamm. Res
                Inflammation Research
                Springer Basel (Basel )
                1023-3830
                1420-908X
                18 December 2013
                18 December 2013
                2014
                : 63
                : 277-285
                Affiliations
                [ ]Department of Biomedical Sciences, 202b Academic and Research Center, Heritage College of Osteopathic Medicine, Ohio University, Athens, OH 45701 USA
                [ ]Department of Biological Sciences, Molecular and Cellular Biology Graduate Program, Ohio University, Athens, USA
                [ ]The Diabetes Institute, Heritage College of Osteopathic Medicine, Ohio University, Athens, USA
                [ ]Department of Internal Medicine, Riverside Methodist Hospital, Columbus, OH USA
                [ ]Mid West Cardiology Research Foundation, Columbus, OH USA
                [ ]Office of Research and Grants, Ohio University, Athens, USA
                [ ]Department of Specialty Medicine, Heritage College of Osteopathic Medicine, Ohio University, Athens, USA
                [ ]Department of Chemical and Biomolecular Engineering, Biomedical Engineering Program, Ohio University, Athens, USA
                Author notes

                Responsible Editor: John Di Battista.

                Article
                697
                10.1007/s00011-013-0697-x
                3950563
                24346141
                © The Author(s) 2013

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

                Categories
                Original Research Paper
                Custom metadata
                © Springer Basel 2014

                Immunology

                tlr2, tlr4, wnt5a, atherosclerosis, inflammation

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