The Role of the CCR1 Receptor During Retinal Degeneration

Abstract

Purpose : Inflammation was implicated in the progression of retinal degeneration. Macrophage's recruitment, partly through the CCR1 receptor, was also associated with the process, and we have recently showed that CCR1 activation in retinal Muller cells plays a role in photoreceptor death in mouse models of retinal injury. Here we aim to further investigate the role of CCR1 in retinal degeneration using Ccr1 genetic deletion and CCR1 inhibition strategies.

Methods : Ccr1^-/-/Crb1^rd8 mice were generated and retinal structure was compared with Crb1^rd8 mice and with wild type mice at the age of 15 months. Readouts included grading of abnormal structure in fundus autofluorescence (FAF) imaging and retinal histological analysis. Retinal inflammation was assessed using real-time quantitative PCR (qPCR) for genes involved in retinal inflammation. Ccr1^-/-/Pde6b^rd10 mice were also generated, and retinal function was compared with Pde6b^rd10 mice, at postnatal day 21 (P21), using electroretinography (ERG). Additionally, CCR1-specific antagonist BX471 (50 mg/kg) or vehicle (40 % cyclodextrin) was administrated to Pde6b^rd10 mice from P21 to P24, every 8 hours via subcutaneous injection followed by ERG recording.

Results : Grading of FAF images in wild type mice, Crb1^rd8 mice, and Ccr1^-/-/Crb1^rd8 mice (n=6 per group), revealed that the deletion of Ccr1 is associated with a decrease of fundus lesions, indicated by the presence of multiple bright spots in the retina. qPCR analysis of Cxcl10, Cxcl1, Ccl2 and F4/80 mRNA levels showed decreased expression in Ccr1^-/-/Crb1^rd8 mice compared with Crb1^rd8 mice (n=6, 0.10; 0.28; 0.24; 0.28-fold change, respectively; p<0.01) and reached the expression level observed in wild-type mice. Deletion of Ccr1 in Pde6b^rd10 mice, was associated with improved retinal function compared with Pde6b^rd10 mice per ERG (n=6, 1.26-fold change; p<0.008). ERG showed that CCR1 blockage with BX471 in Pde6b^rd10 mice, also delayed the course of photoreceptor loss compared with vehicle-treated mice (n=6, 1.88-fold change; p<0.0003).

Conclusions : Ccr1 deletion is associated with diminished retinal injury in rd10 and rd8 models of retinal degeneration. Pharmacologic inhibition of CCR1 conferred a protective effect in the rd10 model. Together, these findings suggest that CCR1 may serve as a novel therapeutic target for retinal degeneration.

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