Reaction of retinal macroglia to inflammatory damage
Authors: Gallardo Meritxell López 
Published: December 2022

AbstractSepsis is a multi‐organ dysfunction caused by the host uncontrolled inflammatory response to an infection, mediated by proinflammatory cytokines and oxygen free radicals. LPS is unable to trespass the Blood–Brain‐Barrier (BBB), but it can act on the TLR4 (Toll‐Like Receptor 4) receptor, found in the endothelium, causing the secretion of cytokines and chemokines that lead to the activation of glial cells. On the other hand, cisplatin (CISP), also called Cis‐dichlorodiammineplatinum [II], is a heavy metal antineoplastic agent widely employed in the treatment of different forms of cancer. Neurotoxicity has been reported as some of the adverse effects resulting from CISP administration. CISP alters intracellular signal transduction pathways that, in the end, provoke apoptosis through different mechanisms such as the generation of reactive oxygen species, DNA alterations, mitochondrial and/or endoplasmic reticulum dysfunction, and the production of proinflammatory cytokines and chemokines. Both sepsis and CISP cause a systemic damage that can result in brain impairments affecting different areas of the Central Nervous System (CNS), but to our knowledge, the effects of the systemic damage over the retinal cell populations, and specially on macroglial cells, have not been studied in detail. We employed two animal models using male Wistar rats: (1) a model of sepsis based on the systemic administration of bacterial lipopolysaccharide (LPS, 10 mg/kg, i.p.), or its vehicle; to induce a systemic inflammatory response; (2) a model of cisplatin based on the administration of a daily single dose of cisplatin (CISP, 5 mg/kg, i.p.) or its vehicle for 5 consecutive days until sacrifice in order to induce neurotoxicity. Animals were transcardiacally perfused, eyes were extracted, and retinal sections were used for immunohistochemical assays, where Brn3a and GFAP were employed to stain retinal ganglion cells and macroglial cells respectively. LPS induced a reduction in the number of Brn3a+ cells in the whole retina, neurodegenerative effects being more critical in the nasal inferior retina; and provoked a generalized increase in GFAP expression, specially in the nasal and central regions of the retina. Preliminary results indicate that the CISP administration leads to a reduction in the total number of Brn3a+ cells in the retina; and CISP may induce a generalized reduction of GFAP+ cells mainly within the nasal and temporal inferior retina. Taken together, we have provided evidence of retinal damage following the systemic inflammatory processes caused by LPS and CISP administration, which affects macroglial cells, with an increased or decreased GFAP expression depending on the activation pathway of the neuroinflammatory response. This dysregulation of the macroglial response could lead to a significant diminishment of the retinal ganglion cells of the retina, causing an irreversible loss of vision.Supported by Complutense University of Madrid, UCM Research Group: 951579.Keywords: LPS‐induced sepsis, cisplatin, ganglionar and macroglial retinal cells, inflammation.