T Cells and Macrophages Responding to Oxidative Damage Cooperate in Pathogenesis of a Mouse Model of Age-Related Macular Degeneration

Cruz-Guilloty, Fernando; Saeed, Ali; Duffort, Stéphanie; Cano, Marisol; Ebrahimi, Katayoon B.; Ballmick, Asha; Tan, Yaohong; Wang, Hua; Laird, James; Salomon, Robert G.; Handa, James T.; Pérez, Víctor L.

doi:10.1371/journal.pone.0088201

Cited by 57 publications

(70 citation statements)

References 59 publications

(81 reference statements)

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“…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].…”

Section: Discussionmentioning

confidence: 99%

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

Chen

Wang

2017

Cell Physiol Biochem

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Background/Aims: Age-related macular degeneration (AMD) is the primary cause of senior blindness in developed countries. Mechanisms underlying initiation and development of AMD remained known. Methods: We examined the CD4 + T cell compartments and their functions in AMD patients. Results: AMD patients presented significantly higher frequencies of interferon (IFN)-γ-expressing and interleukin (IL)-17-expressing CD4 + T cells than healthy controls. The levels of IFN-γ and IL-17 expression by CD4 + T cells were significantly higher in AMD patients. These IFN-γ-expressing Th1 cells and IL-17-expressing Th17 cells could be selectively enriched by surface CCR3 + and CCR4 + CCR6 + expression, respectively. Th1 and Th17 cells from AMD patients promoted the differentiation of monocytes toward M1 macrophages, which were previously associated with retinal damage. Th1 and Th17 cells also increased the level of MHC class I expression in human retinal pigment epithelial (RPE)-1 cells, while Th1 cells increased the frequency of MHC class II-expressing RPE-1 cells. These proinflammatory effects were partly, but not entirely, induced by the secretion of IFN-γ and IL-17. Conclusions: This study demonstrated an enrichment of Th1 cells and Th17 cells in AMD patients. These Th1 and Th17 cells possessed proinflammatory roles in an IFN-γ-and IL-17-dependent fashion, and could potentially serve as therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

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

Chen

Wang

2017

Cell Physiol Biochem

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“…16 Moreover, Th1 cells and the proinflammatory macrophage subset M1 were two of the relevant cell types found in CEP-induced GA animal model. 17 However, the mechanisms of T-cell immunity in the onset of AMD pathology remains unclear.…”

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confidence: 99%

A2E Suppresses Regulatory Function of RPE Cells in Th1 Cell Differentiation Via Production of IL-1β and Inhibition of PGE2

Shi

Qiu

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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Citation: Shi Q, Wang Q, Li J, et al. A2E suppresses regulatory function of RPE cells in Th1 cell differentiation via production of IL-1b and inhibition of PGE2. Invest Ophthalmol Vis Sci. 2015;56:7728-7738. DOI:10.1167/ iovs.15-17677 PURPOSE. Inflammatory status of RPE cells induced by A2E is essential in the development of AMD. Recent research indicated T-cell immunity was involved in the pathological progression of AMD. This study was designed to investigate how A2E suppresses immunoregulatory function of RPE cells in T-cell immunity in vitro. METHODS.Mouse RPE cells or human ARPE19 cells were stimulated with A2E, and co-cultured with naïve T cells under Th1, Th2, Th17, and regulatory T cell (Treg) polarization conditions. The intracellular cytokines or transcript factors of the induced T-cells subset were detected with flow cytometer and qRT-PCR. The ROS levels were detected, and the factors and possible pathways involved in the A2E-laden RPE cells were analyzed through neutralization antibody of IL-1b and inhibitors of related pathways. RESULTS.The A2E reduced regulatory function of RPE cells in Treg differentiation. The A2E-laden RPE cells promoted polarization of Th1 cells in vitro, but not Th2 or Th17 differentiation. The A2E induced RPE cells to release inflammatory cytokines and ROS, but PGE2 production was inhibited. Through neutralization of IL-1b or inhibition of COX2-PGE2 pathways, A2E-laden RPE cells expressed reduced effect in inducing Th1 cells. CONCLUSIONS.The A2E inhibited regulatory function of RPE cells in suppressing Th1 cell immunity in vitro through production of IL-1b and inhibition of PGE2. Our data indicate that A2E could suppress immunoregulatory function of RPE cells and adaptive immunity might play a role in the immune pathogenesis of AMD.

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“…CFH can combine with C3b, inhibiting the formation of alternative-pathway C3 convertase, regulating and controlling the extent of complement activation (Yücel et al, 2012). Environmental factors such as obesity and smoking can interact with the CFH gene polymorphism, leading to reduced CFH expression and activation of the complement system, and therefore significantly increasing the concentrations of C5b-9 (membrane attack complex) and C3b (Atmaca et al, 2011;Schmitz-Valckenberg et al, 2011;Cruz-Guilloty et al, 2014). C5b-9 is deposited on the basement membrane of retinal pigment epithelium (RPE) cells, accelerating the formation of drusen.…”

Section: Discussionmentioning

confidence: 99%

Clinical study of the correlation between complement factor H polymorphism and age-related macular degeneration

Dong

Zhang

et al. 2016

Genet. Mol. Res.

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ABSTRACT. This study aimed to investigate the correlation between age-related macular degeneration (AMD) of the liver-kidney yindeficiency type and complement factor H (CFH) polymorphism, and to determine whether the C allele of the T1277C (Y402H) variant is a risk factor for this condition. We performed a case-control investigation of 60 patients with liver-kidney yin-deficiency AMD and 60 normal control subjects. Peripheral blood was collected from each participant for DNA extraction. Following amplification by polymerase chain reaction, the DNA samples were sequenced, and polymorphism of the CFH gene was examined. Data were analyzed with the chi-square test, with P < 0.05 signifying statistical significance. The frequency of the C allele was significantly higher in the wet than in the dry AMD group (P = 0.044). In addition, the TC and CC genotypes were markedly more common in the former than in the control group (P = 0.013), and there was a significant difference in the distribution of the T and C alleles between wet AMD patients and control subjects (P < 0.05). Based on this, we conclude that liver-kidney yin-deficiency AMD is associated with the C allele and TC and CC genotypes of the CFH Y402H polymorphism. Among patients with this condition, CFH genotypes were normally distributed. The principal CFH genotypes that induce liver-kidney yin-deficiency AMD are the mutant homozygote CC and heterozygote TC forms. Moreover, C allele carriers are at higher risk of developing this disease.

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T Cells and Macrophages Responding to Oxidative Damage Cooperate in Pathogenesis of a Mouse Model of Age-Related Macular Degeneration

Cited by 57 publications

References 59 publications

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

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

A2E Suppresses Regulatory Function of RPE Cells in Th1 Cell Differentiation Via Production of IL-1β and Inhibition of PGE2

Clinical study of the correlation between complement factor H polymorphism and age-related macular degeneration

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