Knockout of ccr2 alleviates photoreceptor cell death in a model of retinitis pigmentosa

Abstract

Neuroinflammation involving CC chemokines such as monocyte chemoattractant protein-1 (MCP-1) has been demonstrated in the pathological process of retinitis pigmentosa (RP), an inherited degenerative retinal disease. However, the mechanism of MCP-1 and its receptor CCR2 involvement in the disease remains unclear. To investigate the role of MCP1/CCR2 in RP pathogenesis, ccr2 mutant RP mice (ccr2(-/-) rd10) were created and analyzed. The expression of MCP-1, RANTES, stromal cell-derived factor (SDF-1), and tumor necrosis factor-α (TNF-α) in the retinas of wild-type, rd10, and ccr2(-/-) rd10 mice was analyzed using quantitative RT-PCR. Photoreceptor apoptosis (TUNEL staining) and the number of microglia (positive for the F4/80 antibody) in the retina were examined. Retinal function was assessed using electroretinograms, and the structure of the whole retina was analyzed from images obtained using optical coherence tomography (OCT) and by histological examination. The expression levels of MCP-1, RANTES, and SDF-1 increased with time in the rd10 mice but not in the wild-type mice. Rearing the mice in the dark prevented degeneration and resulted in thicker photoreceptor layers at each time point. In those mice, the peaks of chemokine expression shifted to a later time with degeneration, suggesting that the expression of these chemokines was induced during the progression of degeneration. Although the difference was not so obvious, the retina in the ccr2(-/-) rd10 mice was consistently and significantly thicker than that in the rd10 (ccr2(+/+) rd10) mice at all time points. Rhodopsin gene expression was also higher in the ccr2(-/-) rd10 mice than in rd10 (ccr2(+/+) rd10) mice, suggesting photoreceptor survival in the former. Retinal function was also better preserved in the ccr2(-/-) rd10 mice than in the rd10 mice. The number of microglia in the retinas of the ccr2(-/-) rd10 mice was significantly lower than that in the retinas of the rd10 mice. Interestingly, the MCP-1 induction that was observed in the retinas of the rd10 mice was diminished in the retinas of the ccr2(-/-) rd10 mice. Our results suggest that the MCP-1/CCR2 system plays a role in retinal degeneration in rd mouse retinas. Retinal MCP-1 expression in the rd mouse retina may be partially controlled by ccr2-positive circulating cells.

Knockout of Ccr2 alleviates photoreceptor cell death in rodent retina exposed to chronic blue light

“…43, 44, 45 As a pivotal chemokine for microglia, Ccr2 has revealed its essential pathogenic role in studies of various inflammatory and degenerative diseases. 27, 46, 47, 48, 49 In the present study, Ccr2 −/− mice with exposure to blue light had significantly reduced infiltration of microglial cells into the retina. These findings suggest an essential role of Ccr2 in the pathogenesis of microglia-mediated degenerative disease, which is consistent with previous reports that Ccr2 is required for efficient recruitment of peripheral monocytes to the pathological tissues in autoimmune uveitis, 46 retinitis pigmentosa, 48 autoimmune encephalitis, 47 and atherosclerosis.…”

Reduced photoreceptor death and improved retinal function during retinal degeneration in mice lacking innate immunity adaptor protein MyD88

“…Pro-inflammatory chemokines are upregulated during retinal degeneration and are thought to contribute to photoreceptor apoptosis (Guo et al, 2012; Kohno et al, 2014; Rutar et al, 2012). To investigate whether removing MyD88-mediated innate immunity signaling pathways blocks expression of these potentially destructive molecules in the presence of a mutation, we compared rd1 mice with a genetic deletion of MyD88 ( rd1/MyD88 -/- ) with their littermates that had intact MyD88 ( rd1/MyD88 +/+ ).…”

“…Increased retinal Ccl2, Ccl3, Ccl4 and Ccl12 were detected in mouse models of AMD and light-induced retinal degeneration (Kohno et al, 2014) and increased Ccl2-Ccl5 and Ccl7 expression were observed prior to and during photoreceptor loss in the rd1 mouse (Zeng et al, 2005). Additionally, in retinal degeneration 10 ( rd10 ) mice that genetically lacked CCR2 , there was improved retinal function and structure (Guo et al, 2012), suggesting that pro-inflammatory chemokines are active participants in the pathology of retinal degeneration. Expression of Ccl2, Ccl4, Ccl5, Ccl7 and Cxcl10 and TNF-α transcripts were reduced in rd1/MyD88 -/- compared with rd1/MyD88 +/+ mice, and maximal expression levels attained in the rd1/MyD88 -/- mice did not reach those of rd1/MyD88 +/+ at the time-points analyzed.…”

CCL3 Production by Microglial Cells Modulates Disease Severity in Murine Models of Retinal Degeneration

“…Conversely, CCL2 and CCR2 were found to have a harmful role in chronic oxidative stress induced or inherited retinal degeneration as Cc2 and Ccr2 gene knockout mice had less severe retinal degeneration (43, 44). In the current study, increased expression of Ccl2 in light-exposed Abca4 -/- Rdh8 -/- mice was observed, in addition to decreased retinal degeneration in Ccl2 -/- Abca4 -/- Rdh8 -/- mice and in the Ccl2 -/- Mertk -/- mouse were demonstrated.…”