Loss of Fas Receptor Function Preserves Photoreceptor Structure and Function in Two Mouse Models of Inherited Retinal
Jingyu Yao1, Tiantian Wang1,2, Lin Jia1
1Department of Ophthalmology and Visual Sciences, University of Michigan Medical School, Kellogg Eye Center, Ann Arbor, Michigan, United States.
Purpose:
The genetic heterogeneity of inherited retinal degeneration (IRD) has limited the development of mutation-specific therapies, necessitating the development of therapeutic approaches targeting broadly shared pathophysiologic pathways. The Fas receptor has been reported as a contributor to retinal cell death and inflammation in a wide variety of ocular diseases. The purpose of this study was to assess targeting the Fas pathway as a novel mutation-independent approach to improve photoreceptor survival in IRD.
Methods:
We examined the effects of genetic inactivation of the Fas receptor on retinal degeneration in two distinct IRD mouse models, P23H and rd10. The Fas-lpr mouse, which contains a functionally inactive Fas receptor, was crossed with the P23H and rd10 mice to generate P23H/Fas-lpr and rd10/Fas-lpr mice. Fas activation, photoreceptor survival and retinal function were assessed.
Results:
We detected elevated levels of Fas receptor and microglial activation in the retinas of both P23H and rd10 mice. Inactivation of Fas in these two IRD models (P23H/Fas-lpr and rd10/Fas-lpr mice) resulted in reduced cell death, increased photoreceptor survival, improved retinal function, and reduced microglial activation and inflammatory cytokine production.
Conclusions:
The protective effect of a nonfunctional Fas receptor in two different mouse models of retinal degeneration suggests that whereas the individual IRD mutation may be specific, the retina's response to the different stressors appears to be shared and driven by Fas. Reducing Fas activity might represent a potential mutation-independent therapeutic approach to preserve retinal structure and function in patients with IRD.
Insights
Targeting the Fas receptor pathway may offer a new treatment for inherited retinal degeneration (IRD). Inactivating Fas protected photoreceptor cells and improved vision in mouse models, suggesting a mutation-independent therapy for IRD.
Area of Science:
- Ophthalmology
- Genetics
- Immunology
Background:
- Inherited retinal degeneration (IRD) presents genetic heterogeneity, complicating mutation-specific therapies.
- Therapeutic strategies for IRD require approaches targeting shared pathological pathways.
- The Fas receptor is implicated in retinal cell death and inflammation across various ocular diseases.
Purpose of the Study:
- To evaluate targeting the Fas pathway as a novel, mutation-independent therapeutic strategy for IRD.
- To investigate the potential of modulating Fas receptor activity to enhance photoreceptor survival in IRD.
Main Methods:
- Utilized two distinct IRD mouse models: P23H and rd10.
- Generated P23H/Fas-lpr and rd10/Fas-lpr mice by crossing IRD models with Fas-lpr mice (lacking functional Fas receptor).
- Assessed Fas activation, photoreceptor survival, and retinal function in the generated mouse models.
Main Results:
- Elevated Fas receptor and microglial activation were observed in P23H and rd10 mouse retinas.
- Fas inactivation in P23H/Fas-lpr and rd10/Fas-lpr mice led to decreased cell death and enhanced photoreceptor survival.
- Retinal function improved, accompanied by reduced microglial activation and inflammatory cytokine production in Fas-inactivated mice.
Conclusions:
- Nonfunctional Fas receptor conferred protection in two different IRD mouse models.
- The retina's response to IRD stressors appears shared and Fas-driven, despite individual mutation specificity.
- Reducing Fas activity presents a potential mutation-independent therapeutic avenue for preserving retinal structure and function in IRD patients.
