Chronic neuroinflammation is increasingly implicated in the progression of neurodegenerative diseases, yet the mechanisms linking metabolic stress, innate immune activation, and neuronal vulnerability remain incompletely defined. Retinitis pigmentosa (RP), despite its genetic heterogeneity, exhibits convergent inflammatory and metabolic alterations during disease progression, providing a useful model for studying immune-mediated neurodegeneration. This review summarizes current evidence from experimental models of retinal degeneration and human retinal studies to examine how sustained neuroinflammation is established in RP. We focus on the coordinated roles of retinal microglia and Müller glia in sensing photoreceptor stress and shaping the inflammatory microenvironment. Microglia are activated early in disease and contribute to progression through inflammatory signaling, phagoptosis, metabolic adaptation, and inflammasome-associated pathways. Müller glia, in turn, modulate metabolic homeostasis and propagate inflammatory signals across retinal layers. We also discuss how stress-responsive regulatory pathways, including p53-associated signaling, influence redox balance, iron handling, and inflammatory persistence without acting as primary apoptotic drivers. Together, these findings support a model in which chronic immunometabolic dysregulation contributes to retinal degeneration and highlight inflammation-related processes as potential targets for mutation-independent therapeutic strategies.
Yang et al. (Sat,) studied this question.