Complement expression in retinal pigment epithelial cells is modulated by activated macrophages

Luo, Chang; Zhao, Jiawu; Madden, Angelina F.; Chen, Mei; Xu, Heping

doi:10.1016/j.exer.2013.04.016

Cited by 72 publications

(66 citation statements)

References 42 publications

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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%

“…Prior to the induction of retinal lesion, macrophages enriched in the M1 type were found to infiltrate the interphotoreceptor matrix in mice, while in CCR2-deficient mice with no infiltration of macrophages, no retinal lesion was observed [20]. Macrophages also stimulate the expression of complement factors and other inflammatory mediators by RPE cells through soluble macrophage-derived cytokines [21]. Given the association between macrophages and AMD, we examined the effect of Th1 and Th17 cells on macrophage differentiation.…”

Section: Ifn-γ + Th1 Cells and Il-17 + Th17 Cells Were Upregulated Inmentioning

confidence: 99%

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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%

Section: Ifn-γ + Th1 Cells and Il-17 + Th17 Cells Were Upregulated Inmentioning

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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“…Another previous study has demonstrated that activated macrophages promoted the alternative pathway of complement activation in the retina via induction of Factor B and C3 expression on RPE cells during inflammatory conditions. 25 Juel et al 3 investigated the effect of the co-culture of human RPE cells with activated T cells on the complement expression. Their results demonstrated that the co-culture increased mRNA for C3, CFB, CFH, CD46, CD55, CD59, and clusterin.…”

Section: Discussionmentioning

confidence: 99%

Detection of Complement Activators in Immune Attack Eyes After iPS-Derived Retinal Pigment Epithelial Cell Transplantation

Sugita

Makabe

Fujii

et al. 2018

Invest. Ophthalmol. Vis. Sci.

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METHODS. To confirm expression of complement factors in human iPS-RPE cells, we performed flow cytometry, immunohistochemistry, ELISA, and quantitative RT-PCR for the following: C3, C5, CFB (Factor B), C5b-9 (membrane attack complex [MAC]), CFH (Factor H), CFI (Factor I), CD46, CD55, CD59, clusterin, and vitronectin. We also prepared iPS-RPE cells in the presence of recombinant IFN-c, recombinant TNF-a, lipopolysaccharide, supernatants of naïve T cells, and T helper 1 (Th1) cells. For the transplantation, after preparation of iPS-RPE cells from cynomolgus monkeys, the iPS-RPE cells (allografts) were transplanted into the subretinal space in monkeys. After surgery, monkeys were euthanized for IHC evaluation of the retinal section and determination of complement factors (C3, C5, CFB, MAC, and C1q), cytokines, and immunoglobulin G (IgG). RESULTS. Human iPS-RPE cells expressed complement activators and inhibitors. iPS-RPE cellshighly expressed complement factors during inflammatory conditions, especially IFN-c exposure including Th1 cell supernatants. In immune attack eyes after allogeneic iPS-RPE cell transplantation, complement activators such as C3, CFB, C5, and MAC were detected around the host RPE layer, grafted RPE cells, inflammatory retinal lesions, and transplanted subretinal space. In addition, we observed a large number of C1q and IgG double positive and IFN-c positive inflammatory cells in the retinal sections.CONCLUSIONS. iPS-derived RPE cells greatly expressed complement factors. Thus, RPE cells might be activated and produce complement factors after exposure to infiltrating inflammatory cells in the eye.

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“…Along with lipofuscin accumulation, dysregulated inflammation is a hallmark of retinal senescence (27). The complement system comprises ∼20 proteins synthesized by the liver and the RPE (28). Chronic activation of complement is thought to play a role in the development and progression of retinopathies, such as AMD (29).…”

Section: Discussionmentioning

confidence: 99%

Rescue of the Stargardt phenotype in Abca4 knockout mice through inhibition of vitamin A dimerization

Issa

Barnard

Herrmann

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

102

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Stargardt disease, an ATP-binding cassette, subfamily A, member 4 (ABCA4)-related retinopathy, is a genetic condition characterized by the accelerated accumulation of lipofuscin in the retinal pigment epithelium, degeneration of the neuroretina, and loss of vision. No approved treatment exists. Here, using a murine model of Stargardt disease, we show that the propensity of vitamin A to dimerize is responsible for triggering the formation of the majority of lipofuscin and transcriptional dysregulation of genes associated with inflammation. Data further demonstrate that replacing vitamin A with vitamin A deuterated at the carbon 20 position (C20-D 3 -vitamin A) impedes the dimerization rate of vitamin A-by approximately fivefold for the vitamin A dimer A2E-and subsequent lipofuscinogenesis and normalizes the aberrant transcription of complement genes without impairing retinal function. Phenotypic rescue by C20-D 3 -vitamin A was also observed noninvasively by quantitative autofluorescence, an imaging technique used clinically, in as little as 3 months after the initiation of treatment, whereas upon interruption of treatment, the age-related increase in autofluorescence resumed. Data suggest that C20-D 3 -vitamin A is a clinically amiable tool to inhibit vitamin A dimerization, which can be used to determine whether slowing the dimerization of vitamin A can prevent vision loss caused by Stargardt disease and other retinopathies associated with the accumulation of lipofuscin in the retina.S targardt disease, first described in 1909, is an autosomal recessive macular dystrophy affecting ∼1 in 10,000 people. The majority of people affected by the disease present with uncorrectable, decreased visual acuity during their teenage years, which most often progresses to legal blindness. To date, there is no approved intervention. Stargardt disease is marked by premature accumulation of lipofuscin in the retinal pigment epithelium (RPE), degeneration of the neuroretina, and subsequent loss of vision. The condition results from mutations in the ATPbinding cassette, subfamily A, member 4 (ABCA4) gene (1), which encodes a transmembrane flippase localized in photoreceptor outer segments. The flippase transports the phosphatidyl-ethanolamineretinaldehyde Schiff base between the cytosol and the cytoplasmic disk surfaces (2). Mutations in ABCA4 also result in retinitis pigmentosa and cone-rod dystrophy and have been linked to age-related macular degeneration (AMD) (3, 4).The accumulation of lipofuscin in the RPE is a common denominator in retinopathies associated with mutations in the ABCA4 gene. Also known as "wear and tear pigment," lipofuscin accumulates as a byproduct of cumulative damage during aging. The brown-yellow, autofluorescent, electron-dense material is also found in cells of the liver, kidney, heart muscle, adrenals, nerve, and ganglion and is considered one of the most consistent morphologic features of aging with a rate of accumulation inversely related to longevity (5, 6). In Stargardt disease, changes in RPE lipof...

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Complement expression in retinal pigment epithelial cells is modulated by activated macrophages

Cited by 72 publications

References 42 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

Detection of Complement Activators in Immune Attack Eyes After iPS-Derived Retinal Pigment Epithelial Cell Transplantation

Rescue of the Stargardt phenotype in Abca4 knockout mice through inhibition of vitamin A dimerization

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