Crucial role of CD33 in microglial responses and photoreceptor survival in a mouse model of retinitis pigmentosa

Abstract

Retinitis pigmentosa (RP) comprises a group of inherited retinal degenerative diseases characterized by the progressive loss of photoreceptors. Neuroinflammation mediated by microglia contributes to the pathophysiology of RP and influences photoreceptor survival. Recent research has emphasized the regulatory function of CD33 (Siglec-3), a surface receptor crucial for microglial responses in multiple neurodegenerative diseases. Here, we expanded our understanding of CD33 in modulating diverse microglial responses during retinal degeneration using the rd10 mouse model of RP. Our findings revealed CD33 downregulation in microglia during photoreceptor degeneration in rd10 mice. CD33 knockout in rd10 mice (CD33-/-;rd10) exacerbated photoreceptor apoptosis and microgliosis, while CD33 overexpression via AAV delivery ameliorated photoreceptor loss and microgliosis, suggesting a protective role of CD33 in RP progression. Moreover, we studied the microglial transcriptomic profile via single cell RNA-sequencing (scRNA-seq) analysis in rd10 and CD33-/-;rd10 mice. CD33 deficiency promoted a dynamic microglial phenotype transition from homeostatic phenotype toward a disease-associated microglia (DAM) phenotype characterized by enhanced phagocytic activity, with downregulation of genes related to homeostasis and upregulation of genes related to lysosome, phagosome, and lipid metabolism. Additionally, CD33 deficiency increased microglial proliferation potential, particularly at the early stages of microglial responses to photoreceptor degeneration. Conversely, CD33 deficiency hindered the transition of microglia to proinflammatory states in the later stages of RP, suppressing Nf-kB signaling to attenuate the production of proinflammatory factors. Further investigations indicated Dab2 as a potential mediator in CD33’s regulation of microglial phenotype transitions. Together, we demonstrated that CD33 plays a critical role in controlling diverse microglial responses including phagocytosis, proliferation, and inflammation during retinal degeneration. Our study provides evidence to support CD33 as a promising therapeutic target for RP.