Schmalen Adrian, Lorenz Lea, Grosche Antje, Pauly Diana, Deeg Cornelia A, Hauck Stefanie M
Research Unit Protein Science and Metabolomics and Proteomics Core, Helmholtz Center Munich, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.
Chair of Physiology, Department of Veterinary Sciences, LMU Munich, Martinsried, Germany.
Front Pharmacol. 2021 Oct 29;12:771571. doi: 10.3389/fphar.2021.771571. eCollection 2021.
Müller cells are the main macroglial cells of the retina exerting a wealth of functions to maintain retinal homoeostasis. Upon pathological changes in the retina, they become gliotic with both protective and detrimental consequences. Accumulating data also provide evidence for a pivotal role of Müller cells in the pathogenesis of diabetic retinopathy (DR). While microglial cells, the resident immune cells of the retina are considered as main players in inflammatory processes associated with DR, the implication of activated Müller cells in chronic retinal inflammation remains to be elucidated. In order to assess the signaling capacity of Müller cells and their role in retinal inflammation, we performed in-depth proteomic analysis of Müller cell proteomes and secretomes after stimulation with INFγ, TNFα, IL-4, IL-6, IL-10, VEGF, TGFβ1, TGFβ2 and TGFβ3. We used both, primary porcine Müller cells and the human Müller cell line MIO-M1 for our hypothesis generating approach. Our results point towards an intense signaling capacity of Müller cells, which reacted in a highly discriminating manner upon treatment with different cytokines. Stimulation of Müller cells resulted in a primarily pro-inflammatory phenotype with secretion of cytokines and components of the complement system. Furthermore, we observed evidence for mitochondrial dysfunction, implying oxidative stress after treatment with the various cytokines. Finally, both MIO-M1 cells and primary porcine Müller cells showed several characteristics of atypical antigen-presenting cells, as they are capable of inducing MHC class I and MHC class II with co-stimulatory molecules. In line with this, they express proteins associated with formation and maturation of phagosomes. Thus, our findings underline the importance of Müller cell signaling in the inflamed retina, indicating an active role in chronic retinal inflammation.
缪勒细胞是视网膜主要的大胶质细胞，发挥着众多维持视网膜稳态的功能。视网膜发生病理变化时，它们会发生胶质化，产生保护和有害两种后果。越来越多的数据也证明缪勒细胞在糖尿病视网膜病变（DR）发病机制中起关键作用。虽然视网膜常驻免疫细胞小胶质细胞被认为是与DR相关炎症过程的主要参与者，但活化的缪勒细胞在慢性视网膜炎症中的作用仍有待阐明。为了评估缪勒细胞的信号传导能力及其在视网膜炎症中的作用，我们在用INFγ、TNFα、IL-4、IL-6、IL-10、VEGF、TGFβ1、TGFβ2和TGFβ3刺激后，对缪勒细胞蛋白质组和分泌蛋白质组进行了深入的蛋白质组学分析。我们使用原代猪缪勒细胞和人缪勒细胞系MIO-M1进行我们的假设生成方法。我们的结果表明缪勒细胞具有强大的信号传导能力，在用不同细胞因子处理时会以高度有区别的方式做出反应。缪勒细胞的刺激导致主要的促炎表型，伴有细胞因子和补体系统成分的分泌。此外，我们观察到线粒体功能障碍的证据，这意味着在用各种细胞因子处理后存在氧化应激。最后，MIO-M1细胞和原代猪缪勒细胞都表现出非典型抗原呈递细胞的几个特征，因为它们能够诱导带有共刺激分子的MHC I类和MHC II类。与此一致的是，它们表达与吞噬体形成和成熟相关的蛋白质。因此，我们的发现强调了缪勒细胞信号传导在炎症视网膜中的重要性，表明其在慢性视网膜炎症中发挥积极作用。
