Inhibition of Microglial CSF1R signaling ameliorates neuroinflammation and photoreceptor degeneration in retinitis pigmentosa

Abstract

Purpose : Neuroinflammation plays a critical role in the pathogenesis of Retinitis pigmentosa (RP), a retinal photoreceptor degenerative disease. Previous studies reported that microglial colony-stimulating factor receptor (CSF1R) signaling was involved in regulating neuroinflammation. However, it remains unclear whether CSF1R signaling contributes to the pathological process of RP. Here, we investigated the roles of CSF1R signaling in neuroinflammation and photoreceptor degeneration in the rd10 mouse model of RP.

Methods : We treated rd10 mice with a CSF1R specific antibody or CSF1R inhibitor PLX5622. Meanwhile, we treated rd10 mice with a recombinant CSF1 or IL-34 protein to investigate the role of the two classical ligands of CSF1R. Moreover, we evaluated relative contribution of microglial proliferation and infiltration to the expansion of the retinal microglial population in RP by injecting clodronate liposomes in rd10 mice and DTT in CX3CR1^CreER/+/R26^iDTR/+/rd10 mice following tamoxifen treatment.

Results : We observed that the inhibition of CSF1R signaling by using a CSF1R specific antibody or PLX5622 treatment significantly inhibited microglia activation and neuroinflammation in rd10 retinas. Meanwhile, we observed that the inhibition of CSF1R signaling markedly downregulated CSF1, IL-34, PU.1 and C/EBPα expressions, indicating that CSF1R signaling pathway was involved in the pathogenesis of RP. Moreover, we found that treatment with recombinant IL-34 or CSF1 proteins in the rd10 retina significantly promoted microglia activation via upregulating CSF1R signaling, suggesting that both CSF1/CSF1R and IL-34/CSF1R signalings could be involved in regulating neuroinflammation in RP. Furthermore, we observed that clodronate liposomes treatment on rd10 mice notably inhibited microglia proliferation and vision decline, indicating that infiltration of peripheral macrophage/microglia might contribute to photoreceptor degeneration. Meanwhile, we observed that the numbers of Iba1⁺/GFP⁺ microglia were significantly less in CX3CR1^CreER/+/R26^iDTR/+/rd10 mice after DTT and tamoxifen treatments, suggesting that repopulated microglia in the rd10 retina are mainly from microglial proliferation.

Conclusions : Our data demonstrated that microglia CSF1R signaling was involved in the pathogenesis of RP. Targeting CSF1R signal could be a new therapeutic strategy for combating RP.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.