Retinal Mueller glial cells trigger the hallmark inflammatory process in autoimmune uveitis.
Abstract: Spontaneous equine recurrent uveitis (ERU) is an incurable autoimmune disease affecting the eye. Although retinal-autoantigen specific T-helper 1 cells have been demonstrated to trigger disease progression and relapses, the molecular processes leading to retinal degeneration and consequent blindness remain unknown. To elucidate such processes, we studied changes in the total retinal proteome of ERU-diseased horses compared to healthy controls. Severe changes in the retinal proteome were found for several markers for blood-retinal barrier breakdown and whose emergence depended upon disease severity. Additionally, uveitic changes in the retina were accompanied by upregulation of aldose 1-epimerase, selenium-binding protein 1, alpha crystallin A chain, phosphatase 2A inhibitor (SET), and glial fibrillary acidic protein (GFAP), the latter indicating an involvement of retinal Mueller glial cells (RMG) in disease process. To confirm this, we screened for additional RMG-specific markers and could demonstrate that, in uveitic retinas, RMG concomitantly upregulate vimentin and GFAP and downregulate glutamine synthetase. These expression patterns suggest for an activated state of RMG, which further downregulate the expression of pigment epithelium-derived factor (PEDF) and begin expressing interferon-gamma, a pro-inflammatory cytokine typical for T-helper 1 cells. We thus propose that RMG may play a fatal role in uveitic disease progression by directly triggering inflammatory processes through the expression and secretion of interferon-gamma.
Publication Date: 2007-04-20 PubMed ID: 17444670DOI: 10.1021/pr060668yGoogle Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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The research study investigates the role of Retinal Mueller glial cells in the progression of Spontaneous equine recurrent uveitis, an autoimmune eye disease. It suggests that these cells could instigate the inflammatory processes that result in retinal degeneration and blindness, providing a novel perspective towards understanding and potentially treating the condition.
Research Context
- Spontaneous equine recurrent uveitis (ERU) is an autoimmune disease affecting the eyes, specifically of horses, that currently has no known cure. It’s known that specific T-helper cells are involved in the disease progression, but the specific molecular mechanisms leading to retinal degeneration and resulting blindness are not yet clear.
Research Methodology and Findings
- The research involved studying changes in the total retinal proteome (the complete set of proteins in the retina) in ERU-affected horses compared to healthy controls.
- The researchers found significant changes in retinal proteins related to the disruption of the blood-retinal barrier, and these changes were linked to the severity of the disease.
- They also observed that certain changes in the retina were associated with an increase in specific markers, including aldose 1-epimerase, selenium-binding protein 1, alpha crystallin A chain, phosphatase 2A inhibitor (SET), and glial fibrillary acidic protein (GFAP).
- The increase in GFAP, in particular, suggested involvement of Retinal Mueller glial cells (RMG) in the disease process.
Role of Retinal Mueller Glial Cells
- Further analysis revealed that in uveitic retinas (retinas affected by uveitis), RMGs have increased levels of vimentin and GFAP but decreased levels of glutamine synthetase. This indicates an activated state of RMGs.
- Activated RMGs downregulate the expression of pigment epithelium-derived factor (PEDF) and start expressing interferon-gamma, a pro-inflammatory cytokine typically associated with T-helper 1 cells.
- This suggests that RMG could directly trigger inflammatory processes in the eye by expressing and secreting interferon-gamma.
Research Impact
- The research provides valuable insights into the potential role of RMGs in the progression of ERU. Recognizing RMGs as a possible trigger of the inflammatory processes linked to ERU marks a significant step towards understanding this complex disease.
- Moreover, this new understanding could provide a platform for exploring novel treatment strategies aimed at modulating the activity of RMG to prevent or slow down ERU progress.
Cite This Article
APA
Hauck SM, Schoeffmann S, Amann B, Stangassinger M, Gerhards H, Ueffing M, Deeg CA.
(2007).
Retinal Mueller glial cells trigger the hallmark inflammatory process in autoimmune uveitis.
J Proteome Res, 6(6), 2121-2131.
https://doi.org/10.1021/pr060668y Publication
Researcher Affiliations
- Institute of Human Genetics, GSF-National Research Center for Environment and Health, Ingolstaedter Landstr. 1, D-85764 Neuherberg, Germany. hauck@gsf.de
MeSH Terms
- Animals
- Autoimmune Diseases / immunology
- Autoimmune Diseases / veterinary
- Cytokines / analysis
- Eye Proteins / analysis
- Horse Diseases / immunology
- Horses / immunology
- Interferon-gamma / analysis
- Nerve Growth Factors / analysis
- Neuroglia / chemistry
- Neuroglia / immunology
- Proteome / analysis
- Retina / chemistry
- Retina / immunology
- Serpins / analysis
- Up-Regulation
- Uveitis / immunology
- Uveitis / veterinary
Citations
This article has been cited 22 times.- Wang Q, Gong Y, Ma X, Fu X, Li R, Qiu K, Wang Y, Zhao Q, Li L, Huang Q, Gao L, Hu X, Zhou X, Zhong J. Aquaporin-4 triggers inflammation in a murine endotoxin-induced uveitis (EIU) model. BMC Ophthalmol 2025 Jul 1;25(1):372.
- Fleischer AB, Amann B, von Toerne C, Degroote RL, Schmalen A, Weißer T, Hauck SM, Deeg CA. Differential Expression of ARG1 and MRC2 in Retinal Müller Glial Cells During Autoimmune Uveitis. Biomolecules 2025 Feb 14;15(2).
- Prieto-López L, Pereiro X, Vecino E. The mechanics of the retina: Müller glia role on retinal extracellular matrix and modelling. Front Med (Lausanne) 2024;11:1393057.
- Yu H, Zhong Z, Zhao Y, Luo H, Sun J, Wang R, Zhang X, Sun X. Insights into myopic choroidal neovascularization based on quantitative proteomics analysis of the aqueous humor. BMC Genomics 2023 Dec 12;24(1):767.
- Schmalen A, Lorenz L, Grosche A, Pauly D, Deeg CA, Hauck SM. Proteomic Phenotyping of Stimulated Müller Cells Uncovers Profound Pro-Inflammatory Signaling and Antigen-Presenting Capacity. Front Pharmacol 2021;12:771571.
- 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.
- Bansal R, Gupta A. Protein Biomarkers in Uveitis. Front Immunol 2020;11:610428.
- Zhuang X, Ma J, Xu S, Sun Z, Zhang R, Zhang M, Xu G. SHP-1 suppresses endotoxin-induced uveitis by inhibiting the TAK1/JNK pathway. J Cell Mol Med 2021 Jan;25(1):147-160.
- Sauter MM, Kolb AW, Brandt CR. Toll-like receptors 4, 5, 6 and 7 are constitutively expressed in non-human primate retinal neurons. J Neuroimmunol 2018 Sep 15;322:26-35.
- Deeg CA, Amann B, Lutz K, Hirmer S, Lutterberg K, Kremmer E, Hauck SM. Aquaporin 11, a regulator of water efflux at retinal Müller glial cell surface decreases concomitant with immune-mediated gliosis. J Neuroinflammation 2016 Apr 23;13(1):89.
- Mol JP, Pires SF, Chapeaurouge AD, Perales J, Santos RL, Andrade HM, Lage AP. Proteomic Profile of Brucella abortus-Infected Bovine Chorioallantoic Membrane Explants. PLoS One 2016;11(4):e0154209.
- 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.
- Fischer MD, Goldmann T, Wallrapp C, Mühlfriedel R, Beck SC, Stern-Schneider G, Ueffing M, Wolfrum U, Seeliger MW. Successful subretinal delivery and monitoring of MicroBeads in mice. PLoS One 2013;8(1):e55173.
- Swadzba ME, Hauck SM, Naim HY, Amann B, Deeg CA. Retinal glycoprotein enrichment by concanavalin a enabled identification of novel membrane autoantigen synaptotagmin-1 in equine recurrent uveitis. PLoS One 2012;7(12):e50929.
- 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.
- Kannan R, Sreekumar PG, Hinton DR. Novel roles for α-crystallins in retinal function and disease. Prog Retin Eye Res 2012 Nov;31(6):576-604.
- Deeg CA, Eberhardt C, Hofmaier F, Amann B, Hauck SM. Osteopontin and fibronectin levels are decreased in vitreous of autoimmune uveitis and retinal expression of both proteins indicates ECM re-modeling. PLoS One 2011;6(12):e27674.
- Wang M, Ma W, Zhao L, Fariss RN, Wong WT. Adaptive Müller cell responses to microglial activation mediate neuroprotection and coordinate inflammation in the retina. J Neuroinflammation 2011 Dec 7;8:173.
- Hauck SM, Dietter J, Kramer RL, Hofmaier F, Zipplies JK, Amann B, Feuchtinger A, Deeg CA, Ueffing M. Deciphering membrane-associated molecular processes in target tissue of autoimmune uveitis by label-free quantitative mass spectrometry. Mol Cell Proteomics 2010 Oct;9(10):2292-305.
- Fort PE, Freeman WM, Losiewicz MK, Singh RS, Gardner TW. The retinal proteome in experimental diabetic retinopathy: up-regulation of crystallins and reversal by systemic and periocular insulin. Mol Cell Proteomics 2009 Apr;8(4):767-79.
- Zhang SX, Wang JJ, Dashti A, Wilson K, Zou MH, Szweda L, Ma JX, Lyons TJ. Pigment epithelium-derived factor mitigates inflammation and oxidative stress in retinal pericytes exposed to oxidized low-density lipoprotein. J Mol Endocrinol 2008 Sep;41(3):135-43.
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