Label-free LC-MSMS analysis of vitreous from autoimmune uveitis reveals a significant decrease in secreted Wnt signalling inhibitors DKK3 and SFRP2.
Abstract: Equine recurrent uveitis is a severe and frequent blinding disease in horses which presents with auto-reactive invading T-cells, resulting in the destruction of the inner eye. Infiltration of inflammatory cells into the retina and vitreous is driven by currently unknown guidance cues, however surgical removal of the vitreous (vitrectomy) has proven therapeutically successful. Therefore, proteomic analyses of vitrectomy samples are likely to result in detection of proteins contributing to disease pathogenesis. Vitreous from healthy and ERU diseased horses were directly compared by quantitative mass spectrometry based on label-free quantification of peak intensities across samples. We found a significant upregulation of complement and coagulation cascades and downregulation of negative paracrine regulators of canonical Wnt signalling including the Wnt signalling inhibitors DKK3 and SFRP2. Based on immunohistochemistry, both proteins are expressed in equine retina and suggest localisation to retinal Müller glial cells (RMG), which may be the source cells for these proteins. Furthermore, retinal expression levels and patterns of DKK3 change in response to ERU. Since many other regulated proteins identified here are associated with RMG cells, these cells qualify as the prime responders to autoimmune triggers.
Copyright © 2012 Elsevier B.V. All rights reserved.
Publication Date: 2012-05-23 PubMed ID: 22634081DOI: 10.1016/j.jprot.2012.04.052Google Scholar: Lookup
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- Journal Article
Summary
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The study explores the changes in protein composition in the inner eye as a result of Equine Recurrent Uveitis (ERU), a common blinding disease in horses. Specifically, the research discovered a decrease in two Wnt signalling inhibitors, DKK3 and SFRP2, which could contribute to the pathogenesis of ERU.
Study Overview
- The research focused on Equine recurrent uveitis (ERU), a severe eye disease in horses that often leads to blindness. ERU presents with auto-reactive T-cells that attack and destroy the inner structures of the eye.
- One therapeutic intervention for ERU is the surgical removal of the vitreous, a clear gel that fills the space between the lens and the retina. The removal of vitreous has been found to alleviate symptoms of ERU.
- The researchers believed that examining the protein composition of the vitreous could reveal the presence and concentrations of proteins that drive disease progression.
Methodology
- The team conducted a label-free LC-MSMS analysis (a type of mass spectrometry) of vitreous samples taken from healthy and ERU-affected horses.
- The analysis measured the peak intensities across samples to quantify the concentrations of different proteins.
Findings
- They found significant changes in protein concentrations between healthy and ERU-affected samples.
- Specifically, they discovered an upregulation of proteins associated with complement and coagulation cascades. This suggests an increase of inflammation and blood clotting in the eye.
- More notably, they observed a significant reduction in two Wnt signalling inhibitors, DKK3 and SFRP2. This decrease indicates that Wnt signalling pathways, which regulate cell growth and differentiation, may be affected in ERU.
Implications
- Additional immunohistochemistry analysis showed these two proteins are mainly found in the retina, particularly in the retinal Müller glial cells (RMG). Thus, suggesting that RMG cells could be the prime responders to autoimmune triggers in ERU.
- The findings in this study broaden our understanding of the pathogenic mechanisms of ERU. Moreover, it could help develop therapeutic interventions targeting Wnt signalling pathways for treating ERU.
Cite This Article
APA
Hauck SM, Hofmaier F, Dietter J, Swadzba ME, Blindert M, Amann B, Behler J, Kremmer E, Ueffing M, Deeg CA.
(2012).
Label-free LC-MSMS analysis of vitreous from autoimmune uveitis reveals a significant decrease in secreted Wnt signalling inhibitors DKK3 and SFRP2.
J Proteomics, 75(14), 4545-4554.
https://doi.org/10.1016/j.jprot.2012.04.052 Publication
Researcher Affiliations
- Research Unit Protein Science, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany. hauck@helmholtz-muenchen.de
MeSH Terms
- Animals
- Autoimmune Diseases / metabolism
- Autoimmune Diseases / veterinary
- Chromatography, Liquid / methods
- Down-Regulation
- Horse Diseases / metabolism
- Horses
- Intercellular Signaling Peptides and Proteins / metabolism
- Mass Spectrometry / methods
- Membrane Proteins / metabolism
- Signal Transduction
- Staining and Labeling
- Uveitis / metabolism
- Uveitis / veterinary
- Vitreous Body
- Wnt Proteins / metabolism
Citations
This article has been cited 19 times.- Hoffmann ALC, Hauck SM, Deeg CA, Degroote RL. Pre-Activated Granulocytes from an Autoimmune Uveitis Model Show Divergent Pathway Activation Profiles upon IL8 Stimulation In Vitro. Int J Mol Sci 2022 Aug 23;23(17).
- Wu F, Mao C, Mou X, Xu C, Zheng T, Bu L, Luo X, Lu Q, Wang X. Decreased β-catenin expression contributes to IFNγ-induced chemokine secretion and lymphocyte infiltration in Hashimoto's thyroiditis. Endocr Connect 2022 Feb 28;11(2).
- Kleinwort KJH, Hobmaier BF, Mayer R, Hölzel C, Degroote RL, Märtlbauer E, Hauck SM, Deeg CA. Mycobacterium avium subsp. paratuberculosis Proteome Changes Profoundly in Milk. Metabolites 2021 Aug 20;11(8).
- Lorenz L, Hirmer S, Schmalen A, Hauck SM, Deeg CA. Cell Surface Profiling of Retinal Müller Glial Cells Reveals Association to Immune Pathways after LPS Stimulation. Cells 2021 Mar 23;10(3).
- Degroote RL, Deeg CA. Immunological Insights in Equine Recurrent Uveitis. Front Immunol 2020;11:609855.
- Degroote RL, Weigand M, Hauck SM, Deeg CA. IL8 and PMA Trigger the Regulation of Different Biological Processes in Granulocyte Activation. Front Immunol 2019;10:3064.
- Kleinwort KJH, Hauck SM, Degroote RL, Scholz AM, Hölzel C, Maertlbauer EP, Deeg C. Peripheral blood bovine lymphocytes and MAP show distinctly different proteome changes and immune pathways in host-pathogen interaction. PeerJ 2019;7:e8130.
- Schauer M, Kleinwort KJH, Degroote RL, Wiedemann C, Kremmer E, Hauck SM, Deeg CA. Interaction of septin 7 and DOCK8 in equine lymphocytes reveals novel insights into signaling pathways associated with autoimmunity. Sci Rep 2018 Aug 17;8(1):12332.
- Xue J, Yang J, Yang L, Zhou S, Ji C, Wang X, Yu N, Liu X, Chi S. Dickkopf-1 Is a Biomarker for Systemic Lupus Erythematosus and Active Lupus Nephritis. J Immunol Res 2017;2017:6861575.
- Shi J, Chi S, Xue J, Yang J, Li F, Liu X. Emerging Role and Therapeutic Implication of Wnt Signaling Pathways in Autoimmune Diseases. J Immunol Res 2016;2016:9392132.
- Grosche A, Hauser A, Lepper MF, Mayo R, von Toerne C, Merl-Pham J, Hauck SM. The Proteome of Native Adult Müller Glial Cells From Murine Retina. Mol Cell Proteomics 2016 Feb;15(2):462-80.
- Skeie JM, Roybal CN, Mahajan VB. Proteomic insight into the molecular function of the vitreous. PLoS One 2015;10(5):e0127567.
- Lorber B, Chew DJ, Hauck SM, Chong RS, Fawcett JW, Martin KR. Retinal glia promote dorsal root ganglion axon regeneration. PLoS One 2015;10(3):e0115996.
- Marcos S, Nieto-Lopez F, Sandonìs A, Cardozo MJ, Di Marco F, Esteve P, Bovolenta P. Secreted frizzled related proteins modulate pathfinding and fasciculation of mouse retina ganglion cell axons by direct and indirect mechanisms. J Neurosci 2015 Mar 18;35(11):4729-40.
- Uhl PB, Amann B, Hauck SM, Deeg CA. Novel localization of peripherin 2, the photoreceptor-specific retinal degeneration slow protein, in retinal pigment epithelium. Int J Mol Sci 2015 Jan 26;16(2):2678-92.
- Mahajan VB, Skeie JM. Translational vitreous proteomics. Proteomics Clin Appl 2014 Apr;8(3-4):204-8.
- Euler KN, Hauck SM, Ueffing M, Deeg CA. Bovine neonatal pancytopenia--comparative proteomic characterization of two BVD vaccines and the producer cell surface proteome (MDBK). BMC Vet Res 2013 Jan 23;9:18.
- Szober CM, Hauck SM, Euler KN, Fröhlich KJ, Alge-Priglinger C, Ueffing M, Deeg CA. Profound re-organization of cell surface proteome in equine retinal pigment epithelial cells in response to in vitro culturing. Int J Mol Sci 2012 Oct 31;13(11):14053-72.
- Angi M, Kalirai H, Coupland SE, Damato BE, Semeraro F, Romano MR. Proteomic analyses of the vitreous humour. Mediators Inflamm 2012;2012:148039.
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