Abstract
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.
Highlights
Neurodegenerative diseases of the retina are characterized by progressive retinal damage eventually resulting in vision loss (Duncan et al, 2018)
Whether this privileged position within the retina translates into extensive signaling between Müller cells and the surrounding cells, the secretomes of the human Müller cellderived cell line Moorfields/Institute of Ophthalmology-Müller 1 (MIO-M1) and of porcine retinal Müller Glia (pRMG) were quantitatively analyzed by mass spectrometry after stimulation for 24 h with the cytokines IFNγ, Interleukin 10 (IL-10), Interleukin 4 (IL-4), Interleukin 6 (IL-6), TGFβ1, TGFβ2, TGFβ3, TNFα and Vascular Endothelial Growth Factor165 (VEGF), respectively
While microglial cells are considered as the main drivers of retinal immune responses (Karlstetter et al, 2015), increasing evidence suggests that excessive signaling between Müller cells and microglia affects the inflammatory processes (Wang et al, 2011; Di Pierdomenico et al, 2020)
Summary
Neurodegenerative diseases of the retina are characterized by progressive retinal damage eventually resulting in vision loss (Duncan et al, 2018). Chronic hyperglycemia in diabetes patients induces the activation of leukocytes in the periphery (Chen et al, 2019) as well as micro- and macroglial cells in the retina (Mizutani et al, 1998; Gerhardinger et al, 2005; Zeng et al, 2008). This results in the release of pro-inflammatory cytokines and eventually leads to photoreceptor cell death (Coughlin et al, 2017; Kinuthia et al, 2020). Growing evidence suggests that the interaction of micro- and macroglial cells essentially shapes retinal inflammation and photoreceptor degeneration (Wang et al, 2011; Di Pierdomenico et al, 2020)
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