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

Abstract

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)

Increased Th1/Th17 Responses Contribute to Low-Grade Inflammation in Age-Related Macular Degeneration

“…Many studies in animal models have established causal links between retinal damage and proinflammatory pathways [20][21][22]. In humans, many studies have shown that AMD patients presented higher expression of proinflammatory cytokines and altered phenotype and functions of immune cells [16,23,24]. This study demonstrated that AMD patients also presented an imbalance in the composition of CD4 + T …”

Inflammatory Biomarkers for AMD

“…These chemokines are involved in leukocyte recruitment, and some have been implicated in AMD previously. The intraocular concentration of CCL2 was elevated in wet AMD eyes [32] and in urine from wet AMD patients [34] but there was no significant difference in serum from wet AMD cases compared to controls [35].…”

“…CXCL10 was localised to the choroid in AMD eyes, and significantly elevated CXCL10 concentrations measured in serum from AMD patients of all stages, relative to controls [33]. However, no such difference was observed in a study using a similar number of CNV cases (18) and controls (18) [35]. Larger sample sizes are required to validate CXCL10 as a biomarker for AMD.…”

Retinal Phenotype following Combined Deletion of the Chemokine Receptor CCR2 and the Chemokine CX3CL1 in Mice

“…Mononuclear phagocytes including macrophages and microglia have been implicated in the pathogenesis of age-related macular degeneration (AMD) and other retinal degenerative diseases [1,2,3,4,5,6,7,8,9,10,11,12,13]. While multiple evidence supports such an involvement, macrophages and microglia may possibly have both beneficial and deleterious effects in the context of these diseases [1,14].…”