The role of Müller cell glucocorticoid signaling in diabetic retinopathy

Abstract

Diabetic Retinopathy (DR) is a sight-threatening complication associated with the highly prevalent diabetes disorder. Both the microvascular damage and neurodegeneration detected in the retina caused by chronic hyperglycemia have brought special attention to Müller cells, the major macroglia of the retina that are responsible for retinal homeostasis.Given the role of glucocorticoid signaling in anti-inflammatory responses and the almost exclusive expression of glucocorticoid receptors (GR) in retinal Müller cells, administration of corticosteroid agonists as a potential treatment option has been widely studied. Although these approaches have been moderately efficacious in treating or deescalating DR pathomechanisms, there are various side effects and gaps of knowledge with regards to introducing exogenous glucocorticoids to the diseased retina. In this paper we provide a review of the literature concerning the available evidence for the role of Müller cell glucocorticoid signaling in DR and we discuss previously investigated approaches in modulating this system as possible treatment options. Furthermore, we propose a novel alternative to the available choices of treatment by using gene therapy as a tool to regulate the expression of GR in retinal Müller cells. Upregulating GR expression allows for induced glucocorticoid signaling with more enduring effects compared to injection of agonists. Hence, repetitive injections would no longer be required. Lastly, side effects of glucocorticoid therapy such as glucocorticoid resistance of GR following chronic exposure to excess ligands or agonists can be avoided.

Proteomic Phenotyping of Stimulated Müller Cells Uncovers Profound Pro-Inflammatory Signaling and Antigen-Presenting Capacity

“…It is known that Müller cells are an important source of neurotrophic factors but also of pro-inflammatory and angiogenetic cytokines (Bringmann et al, 2009;Ruzafa et al, 2018;von Toerne et al, 2014;Hauck et al, 2007). They play an important role in DR pathogenesis (Subirada et al, 2018;Ghaseminejad et al, 2020) and it was also suggested that they are involved in retinal immune responses (Roberge et al, 1988;Rutar et al, 2015;Natoli et al, 2017;Lorenz et al, 2021a;Lorenz et al, 2021b). However, the impact of their protective or detrimental effects on retinal inflammation in DR and other neurodegenerative retinal diseases remains elusive so far.…”

Cell Surface Profiling of Retinal Müller Glial Cells Reveals Association to Immune Pathways after LPS Stimulation

“…In recent years, retinal Müller glial cells (RMG) have gained increasing attention, as they are involved in virtually every retinal disease and represent valuable therapeutic targets (reviewed in [1][2][3][4]). RMG are the principal macroglial cells of the retina [5] and span its entire thickness from the inner to the outer limiting membrane [6].…”

Understanding Neurodegeneration from a Clinical and Therapeutic Perspective in Early Diabetic Retinopathy

“…The Müller cells dysfunction may further lead to an excess of glutamate, aggravating the neurotoxicity with neuron death [6,30,[36][37][38][39]. Another consequence of Müller dysfunction is represented by the downregulation of the K+ channel subtype Kir4.1 and aquaporins but not Kir2.1, leading to an anomalous potassium intake and swelling [30,31,40]. The Müller glia are induced under hypoxic condition or glucosedeprived to increase their production and secretion of vascular endothelium growth factor (VEGF), which is also further increased by the altered permeability [23,40,41].…”