Retinal Mueller Glial Cells Trigger the Hallmark Inflammatory Process in Autoimmune Uveitis

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.
Keywords: inflammation • blood-retinal barrier • Mueller glia • autoimmune disease • clinical proteomics • uveitis

自发性马复发性葡萄膜炎（equine recurrent uveitis, ERU）是一种无法治愈的眼部自身免疫性疾病。尽管已有研究证实视网膜自身抗原特异性T辅助1（T helper 1, Th1）细胞可触发疾病进展与复发，但介导视网膜变性乃至最终失明的分子机制仍未明确。为阐明该类机制，本研究对比了ERU患病马与健康对照马的全视网膜蛋白质组变化。结果发现，多项与血-视网膜屏障（blood-retinal barrier, BRB）破坏相关的标志物的视网膜蛋白质组水平发生显著改变，且其表达丰度随疾病严重程度动态变化。此外，视网膜的葡萄膜炎性病理改变伴随有醛糖1-表异构酶、硒结合蛋白1、α晶状体蛋白A链、蛋白磷酸酶2A抑制剂（SET）以及胶质纤维酸性蛋白（glial fibrillary acidic protein, GFAP）的表达上调，其中GFAP的上调提示视网膜Müller胶质细胞（retinal Mueller glial cells, RMG）参与了疾病进程。为验证这一推测，本研究针对额外的RMG特异性标志物开展了筛选，结果证实，在葡萄膜炎性视网膜组织中，RMG会同时上调波形蛋白与GFAP的表达，并下调谷氨酰胺合成酶的表达。上述表达模式提示RMG处于激活状态，这类活化的RMG会进一步下调色素上皮衍生因子（pigment epithelium-derived factor, PEDF）的表达，并开始表达干扰素-γ——一种典型的T辅助1细胞源性促炎细胞因子。据此，本研究提出RMG可能通过表达并分泌干扰素-γ直接触发炎症反应，从而在葡萄膜炎性疾病进展中发挥致命性作用。
关键词：炎症 • 血-视网膜屏障 • Müller胶质细胞 • 自身免疫性疾病 • 临床蛋白质组学 • 葡萄膜炎