Induction of Chemokine Secretion and Monocyte Migration by Human Choroidal Melanocytes in Response to Proinflammatory Cytokines

Jehs, Tina; Faber, Carsten; Udsen, Maja Søberg; Jager, Martine J.; Clark, Simon J.; Nissen, Mogens Holst

doi:10.1167/iovs.15-18524

Cited by 18 publications

(16 citation statements)

References 56 publications

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“…However, recently we have demonstrated that native choroidal melanocytes may harbor similar functionality including secretion of chemokines and suppression of T cell activation. 15 Systemically increased levels of IFN-c from systemic virus infection in rodents has been shown to induce a transient subretinal accumulation of retinal microglia, 16 which indicates that systemic inflammation contributes to the immune status of the chorioretinal interface. The transcriptional response of the choroidal/RPE interface to systemic inflammation has, however, not been explored before.…”

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confidence: 99%

Chemokine Expression in Murine RPE/Choroid in Response to Systemic Viral Infection and Elevated Levels of Circulating Interferon-γ

Faber

Juel

Jensen

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. To examine how circulating immune mediators in vivo may affect gene and protein expression at the RPE/choroid interface. METHODS. Young mice were systemically infected with lymphocytic choriomeningitis virus (LCMV) or continuously infused with IFN-c. RPE/choroid was isolated and analyzed with whole-transcriptome gene expression microarrays. Selected gene expression findings were validated at the protein level. RESULTS. Both the systemic immune activation from virus infection and the sterile systemically increased level of IFN-c resulted in increased expression of chemokine ligands, chemokine receptors, and early complement components in isolates of RPE/choroid. These findings were largely absent from LCMV-infected mice deficient in either the interferon a/b receptor or IFN-c. CONCLUSIONS. Together, these findings demonstrate that acute systemic immune activation results in a local response at the RPE/choroid interface that may include chemokinedependent recruitment of inflammatory cells and engagement of the complement system. This may represent a link between the systemic low-grade inflammation and the retinal pathology observed in several multifactorial entities such as aging, AMD, and diabetes.

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confidence: 99%

Chemokine Expression in Murine RPE/Choroid in Response to Systemic Viral Infection and Elevated Levels of Circulating Interferon-γ

Faber

Juel

Jensen

et al. 2019

Invest. Ophthalmol. Vis. Sci.

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“…The monocyte role was not explored in depth in the present work. However, monocyte migration towards uveal melanocytes after being in contact with conditioned medium from activated T cells that contains increased IFN-γ and TNF-α has been described in vitro 48 . T cells produce those cytokines after T cell receptor stimulation and induce monocyte production of GMCSF.…”

Section: Resultsmentioning

confidence: 99%

Human immunocompetent Choroid-on-Chip: a novel tool for studying ocular effects of biological drugs

Cipriano

Schluender

Probst

et al. 2021

Preprint

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Disorders of the eye leading to visual impairment are a major issue that affects millions of people. On the other side ocular toxicities were described for e.g. molecularly targeted therapies in oncology and may hamper their development. Current ocular model systems feature a number of limitations affecting human-relevance and availability. To find new options for pharmacological treatment and assess mechanisms of toxicity, hence, novel complex model systems that are human-relevant and readily available are urgently required. Here, we report the development of a human immunocompetent Choroid-on-Chip (CoC), a human cell-based in vitro model of the choroid layer of the eye integrating melanocytes and microvascular endothelial cells, covered by a layer of retinal pigmented epithelial cells. Immunocompetence is achieved by perfusion of peripheral immune cells. We demonstrate controlled immune cell recruitment into the stromal compartments through a vascular monolayer and in vivo-like cytokine release profiles. To investigate applicability for both efficacy testing of immunosuppressive compounds as well as safety profiling of immunoactivating antibodies, we exposed the CoCs to cyclosporine and tested CD3 bispecific antibodies.

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“…Another gene, whose expression in the LPS‐stimulated lightly pigmented melanocytes was substantially higher (over 100‐fold at the mRNA transcript level and nearly 2‐fold at the protein level) than in the heavily pigmented cells, was that encoding CCL2 chemokine. CCL2 (monocyte chemotactic protein 1; MCP‐1) is one of the key chemokines that regulate migration and infiltration of monocytes, macrophages and lymphocytes, and has a role in chronic inflammation . Moreover, it stimulates proliferation and migration of endothelial cells and may contribute to the mechanism of increased pathological angiogenesis in lighter skin.…”

Section: Discussionmentioning

confidence: 99%

“…After the LPS treatment, HEMn‐DP secreted much more CXCL8 (IL‐8) than HEMn‐LP, despite the higher expression showed by the latter cells at the mRNA level. The chemokine is involved in the acute inflammatory response in vivo and exhibits a chemotactic activity for neutrophils, T cells, fibroblasts, endothelial cells and melanocytes in vitro . Miniati et al observed increased release of CXCL8 from human melanocytes in response to TNF‐α and IL‐1β, and elevated CXCL8 gene expression in the lesional skin of patients with new‐onset and active vitiligo.…”

Section: Discussionmentioning

confidence: 99%

Differential expression of inflammatory cytokines and chemokines in lipopolysaccharide‐stimulated melanocytes from lightly and darkly pigmented skin

Tam

Dzierżęga‐Lęcznar

Stępień

2019

Experimental Dermatology

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Increasing evidence suggests that human epidermal melanocytes play an important role in the skin immune system; however, a role of their pigmentation in immune and inflammatory responses is poorly examined. In the study, the expression of Toll‐like receptor 4 (TLR4) and inflammatory cytokines and chemokines by cultured normal melanocytes derived from lightly and darkly pigmented skin was investigated after cell stimulation with lipopolysaccharide (LPS). The basal TLR4 mRNA level in heavily pigmented cells was higher as compared to their lightly pigmented counterparts. Melanocyte exposure to LPS upregulated the expression of TLR4 mRNA and enhanced the DNA‐binding activity of NF‐κB p50 and p65. We found substantial differences in the LPS‐stimulated expression of numerous genes encoding inflammatory cytokines and chemokines between the cells with various melanin contents. In lightly pigmented melanocytes, the most significantly upregulated genes were nicotinamide phosphoribosyltransferase (NAMPT/visfatin), the chemokines CCL2 and CCL20, and IL6, while the genes for CXCL12, IL‐16 and the chemokine receptor CCR4 were the most significantly upregulated in heavily pigmented cells. Moreover, the lightly pigmented melanocytes secreted much more NAMPT, CCL2 and IL‐6. The results of our study suggest modulatory effect of melanogenesis on the immune properties of normal epidermal melanocytes.

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Induction of Chemokine Secretion and Monocyte Migration by Human Choroidal Melanocytes in Response to Proinflammatory Cytokines

Abstract: These results showed that normal and activated HCMs are immunologically active by secreting chemokines, and that HCMs are able to attract monocytes in addition to inhibiting T-cell proliferation.

Cited by 18 publications

References 56 publications

Chemokine Expression in Murine RPE/Choroid in Response to Systemic Viral Infection and Elevated Levels of Circulating Interferon-γ

Chemokine Expression in Murine RPE/Choroid in Response to Systemic Viral Infection and Elevated Levels of Circulating Interferon-γ

Human immunocompetent Choroid-on-Chip: a novel tool for studying ocular effects of biological drugs

Differential expression of inflammatory cytokines and chemokines in lipopolysaccharide‐stimulated melanocytes from lightly and darkly pigmented skin

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