Targeting the CCL7-STAT1 axis attenuates microglial neurotoxicity and photoreceptor degeneration in retinitis pigmentosa.

Abstract

Retinitis pigmentosa (RP), the most prevalent inherited retinal degenerative disorder, manifests as progressive and irreversible photoreceptor loss with no approved disease-modifying therapies. Emerging evidence implicates microglia-mediated neuroinflammation as a critical accelerator of RP progression, but its underlying molecular mechanisms remain elusive. Through single-cell RNA sequencing (scRNA-seq) of retinal microglia from the rd10 mouse model of RP, we identified Ccl7 as an important driver of microglial inflammation and defined a distinct subpopulation of CCL7hi microglia as pivotal orchestrators of neuroinflammation and photoreceptor degeneration. Evidently, genetic knockdown of Ccl7 suppressed microglial activation and neuroinflammation, attenuated photoreceptor degeneration, and preserved visual function in rd10 mice, while exogenous CCL7 administration exacerbated microglial reactivity and accelerated photoreceptor apoptosis. Ccl7 upregulation in microglia induced a characteristic senescent signature and promoted pathological phagocytosis, contributing to inflammation and photoreceptor cell death. Mechanistically, microglial Ccl7 trigger a self-amplifying inflammatory cascade by activating STAT1 signaling, and propagate inflammation cascades through CCL7-CCR1/5 inter-microglial communication. Our results establish the CCL7-STAT1 axis as an important regulator of microglial dysfunction in RP. Targeting this pathway represents a promising disease-modifying strategy to halt RP progression, with significant implications for clinical translation.