Macroglial activation over time in an experimental glaucoma model
Authors: Fernández‐Albarral José A. 
Published: December 2022

Glaucoma is a neurodegenerative retinal disease characterized by irreversible loss of retinal ganglion cells (RGCs), leading to visual loss. Increased intraocular pressure (IOP) is the only risk factor for which treatment is available. However, other factors such as glial activation and dysfunction can also induce RGC death in glaucoma.

Astrocytes and Müller glia (macroglial cells) play important roles in neuronal activity by providing physical and metabolic support to neurons. In glaucoma, when tissue damage occurs, macroglial cells undergo reactive gliosis, to defend the nerve tissue against damage and attempt to maintain its homeostasis. However, alterations in the function of these cells could cause damage and even neuronal death. In reactive macrogliosis, cells undergo complex biochemical and functional remodelling and exhibit morphological changes characterized by cell body thickening, increased number and length of cell processes, increased cell number and up‐regulation of cytoskeletal components such as gliofibrillary acidic protein (GFAP), which is considered one of the main markers of this process and may act as antigen‐presenting cells by expressing major histocompatibility complex class II (MHC‐II). Reactivation of macroglia can initially be beneficial, as it increases their metabolic activity, increases the expression of antioxidant defence, and restores ion, water and neurotransmitter balance. However, if macroglia become chronic, it is detrimental by directly or indirectly damaging the tissue and preventing its repair. Astrocytes may act in concert with microglia during the inflammatory process, so inflammatory mediators produced by astrocytes can chronically activate microglial cells, contributing to neuronal death, and similarly, inflammatory mediators released by microglia can chronically activate astrocytes.

One of the most widely used models to elevate IOP is the unilateral laser‐induced ocular hypertension (OHT) model. Studies in this model have analysed the temporal pattern of RGC death and microglial cell activation at time points: 1, 3, 5, 8 and 15 days. Molecular changes in proinflammatory and anti‐inflammatory cytokines involved in the neuroinflammatory process, released by glial cells (microglia, astrocytes, and Müller cells) at the same time points mentioned above, have also been identified.

Given the close relationship between the activation of macroglia and microglia and their involvement in the death of RGCs in this pathology, the present work analysed how the activation of retinal macroglial cells occurred at different time points (1, 3, 5, 8 and 15 days) after the induction of OHT in an experimental model of laser‐induced OHT in mice. For this purpose, we have analysed the GFAP‐labelled retinal area, the intensity of GFAP labelling, and the expression of MHC‐II in both OHT eyes and normotensive contralateral eyes compared to naïve eyes.

In this study, in both OHT and contralateral eyes, macroglial cells showed morphological changes as well as in GFAP and MHC‐II expression at all time points analysed, being slightly more intense at 3–5 days, coinciding with the pattern of microglial activation previously studied, demonstrating this fact, a bilateral inflammatory process maintained over time in which microglia, astrocytes and Müller glia are involved.