CCL2/CCR2 and CX3CL1/CX3CR1 chemokine axes and their possible involvement in age-related macular degeneration

PURPOSE. To elucidate the influences of light exposure on the retinal pigment epithelium (RPE) in vivo that may be involved in the pathogenesis of AMD.METHODS. Six-to 7-week-old BALB/c mice were exposed to light at 2000 lux for 3 hours. Flatmount RPE samples were immunostained with anti-ZO-1 antibody for evaluating tight junction, anti-N-cadherin, and anti-b-catenin antibodies for adherens junction, and stained with phalloidin for actin cytoskeleton. The reactive oxygen species (ROS) level was measured using DCFH-DA; Rho-associated coiled-coil forming kinase (ROCK) activity was by ELISA. RESULTS. Light exposure disrupted staining patterns of tight junctions, adherens junctions, and actin cytoskeleton in the RPE, where ROS was elevated. However, NAC treatment avoided the RPE changes, reducing ROS. ROCK activity increased after light exposure was suppressed by NAC, and the structural disruptions were suppressed by Y-27632. The levels of MCP-1, CCL11, and IL-6 increased after light exposure were suppressed by NAC. Light-induced MCP-1 and IL-6 were suppressed by Y-27632. Macrophage recruitment after light exposure was also suppressed either by NAC or Y-27632.CONCLUSIONS. Light exposure induced ROS and Rho/ROCK activation, which caused disruption of cell-cell junctions (tight junctions and adherens junctions) and actin cytoskeleton, the RPE's barrier structure, and induced AMD-associated pathological changes in the RPE-choroid.

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“…[7][8][9]20 In this study, we showed that light exposure also affected the RPE in vivo, by promoting ROS induction.…”

Section: Discussionmentioning

confidence: 55%

Disruption of Cell-Cell Junctions and Induction of Pathological Cytokines in the Retinal Pigment Epithelium of Light-Exposed Mice

Narimatsu

Ozawa

Miyake

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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“…18,19 Mice with perturbed signaling of CCR2 and CX 3 CR1, two of the major chemokine receptors involved in monocyte recruitment, demonstrate retinal alterations that recapitulate some of the features of AMD. [20][21][22][23] Furthermore, studies have recently shown that several of the chemokine ligands, including CCL2 (the ligand for CCR2, also known as MCP-1, or monocyte chemoattractant protein 1), are present in higher intraocular concentrations in NV-AMD eyes 24 and urine. 25 High levels of CCL2 have been found in RPE in vivo, 26 and this chemokine may be associated with CNV growth in mice.…”

Section: Resultsmentioning

confidence: 99%

Chemokine Receptor Expression in Peripheral Blood Monocytes from Patients with Neovascular Age-Related Macular Degeneration

Grunin

Burstyn‐Cohen

Hagbi-Levi

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Chemokine signaling and monocytes/macrophages were implicated in the pathogenesis of AMD. We tested the association between chemokines involved in monocyte recruitment and AMD. METHODS.Immunophenotyping for white blood cell (WBC) populations including CD14þþCD16-and CD14þCD16þ monocytes, CD19þ, CD3þ, and CD16þ lymphocytes, and chemokine receptors CCR1, CCR2, CCR5, CX 3 CR1, and CXCR4 was performed on peripheral blood from treatment-naïve neovascular AMD (NV-AMD) patients and controls. The mRNA level of chemokine receptors in monocytes was measured with quantitative-PCR. Systemic levels of major chemokine ligands CCL2, CCL5, CCL3, and CXCL10 were evaluated by ELISA. Genotyping was performed for risk SNPs for AMD in the CFH, C3, and HTRA1 genes. RESULTS.The percentage of WBC subpopulations tested was similar between NV-AMD patients (n ¼ 18) and controls (n ¼ 20). CD14þCD16þ monocyte subpopulation showed a 3.5-fold increased expression of CCR1 (P ¼ 0.039; t-test) and a 2.2-fold increased expression of CCR2 (P ¼ 0.027) in patients compared with controls. Increased CCR1 and CCR2 expression was correlated with each other in patients (R 2 ¼ 0.64, P < 0.0001), but not controls (R 2 ¼ 0.02, P ¼ 0.57). Increased mRNA levels of CCR1 (1.6-fold, P ¼ 0.037) and CCR2 (1.6-fold, P ¼ 0.007) were found in monocytes from NV-AMD patients. Chemokine receptor expression was not correlated with the presence of risk SNPs, and was not associated with blood chemokine levels.CONCLUSIONS. CCR1 and CCR2 are coupregulated on the CD14þCD16þ monocyte population in NV-AMD patients. These data implicate CD14þCD16þ monocytes and chemokine signaling in AMD. Additional investigation is needed to elucidate the role of these monocytes and their potential as a biomarker or therapeutic target for AMD. (Invest Ophthalmol Vis Sci. 2012;53:5292-5300)

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“…In addition to PRRs, various other molecules are also involved in microglial activation. Fractalkine (CX3CL1) is constitutively produced by neurons in the CNS, 4,5 including the neural retina, [6][7][8] whereas its receptor CX3CR1 is exclusively expressed by microglial cells. 5,8,9 CX3CL1-CX3CR1 signaling is one of the main pathways involved in neuronmicroglia interactions and plays a crucial role in regulating microglial activation.…”

Section: Discussionmentioning

confidence: 99%

Paraquat-Induced Retinal Degeneration Is Exaggerated in CX3CR1-Deficient Mice and Is Associated with Increased Retinal Inflammation

Chen

Luo²,

Peñalva³

et al. 2013

Invest. Ophthalmol. Vis. Sci.

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PURPOSE.To investigate the role of the Fractalkine receptor CX3CR1 pathway in oxidative insults-mediated retinal degeneration and immune activation. RESULTS. Intravitreal injection of paraquat (0.75 lM) resulted in acute retinal capillary nonperfusion within 2 days, which improved from 4 days to 4 weeks postinjection (p.i.). Panretinal degeneration was observed at 4 days p.i. and progressed further at 4 weeks p.i. In the absence of CX3CR1, retinal degeneration was exaggerated and was accompanied by increased TNF-a, iNOS, IL-1b, Ccl2, and Casp-1 gene expression. Confocal microscopy of retinal flatmounts revealed microglial activation and CD44 þ MHC-II þ monocyte and GR1 þ neutrophil infiltration in paraquat-injected eyes. The number of activated microglia and infiltrating leukocytes was significantly higher in CX3CR1 gfp/gfp mice than in CX3CR1 gfp/þ mice. CONCLUSIONS.Our results suggest that the CX3CR1 signaling pathway may play an important role in controlling retinal inflammation under oxidative and ischemia/reperfusion conditions. In the absence of CX3CR1, uncontrolled retinal inflammation results in exaggerated retinal degeneration. (Invest Ophthalmol Vis Sci. 2013;54:682-690)

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CCL2/CCR2 and CX3CL1/CX3CR1 chemokine axes and their possible involvement in age-related macular degeneration

Cited by 86 publications

References 63 publications

Disruption of Cell-Cell Junctions and Induction of Pathological Cytokines in the Retinal Pigment Epithelium of Light-Exposed Mice

Disruption of Cell-Cell Junctions and Induction of Pathological Cytokines in the Retinal Pigment Epithelium of Light-Exposed Mice

Chemokine Receptor Expression in Peripheral Blood Monocytes from Patients with Neovascular Age-Related Macular Degeneration

Paraquat-Induced Retinal Degeneration Is Exaggerated in CX3CR1-Deficient Mice and Is Associated with Increased Retinal Inflammation

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