Abstract
Purpose :
The retina is an elaborate system of neurons and glia responsible for converting light into an electrical signal that is sent to the brain. This electrical signal utilizes multiple neuronal types beginning with rod and cone photoreceptors and ending with retinal ganglion cells (RGCs) whose axons form the optic nerve. Different retinal neurodegenerative diseases (NDs) preferentially kill specific neuronal types with glaucoma targeting RGCs, diabetic retinopathy targeting RGCs first and other neurons later, maculopathies targeting central retinal cones, and inherited retinal dystrophies (IRDs) targeting rods and cones. Our group has uncovered individual strains of mice from the BXD family, each presenting with different forms of these NDs and have previously shown enhanced inflammation in a severe IRD model. The purpose of this work was to assess if retinal inflammation is induced in these models and to what extent it occurs.
Methods :
We assessed for retinal stress and inflammation in the BXD29, 50, 51, and 87 (models of different forms of glaucoma), BXD34 (a model of progressive photoreceptor degeneration), BXD79 (a model of DR), and C57B/6J controls at 12 months of age using IHC analyses for GFAP (glial fibrillary acidic protein), macrophages (IBA1, ionized calcium binding adaptor molecule 1), TNFα (tumor necrosis factor alpha) and its downstream pathway components NF-κB p65 (nuclear factor-kappa B p65) and NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3), and STAT3 (signal transducer and activator of transcription 3), its phosphorylated form pSTAT3-Y705, and the pathway antagonist SOCS3 (suppressor of cytokine signaling 3).
Results :
IHC revealed that not only do all of the models exhibit proinflammatory upregulation, but, depending on the disease type and severity, also have more or less inflammation with age. The level of inflammation correlated almost directly to disease severity with the order observed being BXD29<BXD87<BXD50<BXD51<BXD79<BXD34. These levels of inflammation were applicable to the majority of the markers tested.
Conclusions :
The BXD mouse models for glaucoma, photoreceptor degeneration, and DR, while presenting as high fidelity, spontaneous models of retinal NDs, display varying degrees of retinal inflammation and these levels are dependent on the severity of the degenerative phenotype.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.