<i>Cis</i>-urocanic acid, a sunlight-induced immunosuppressive factor, activates immune suppression via the 5-HT<sub>2A</sub>receptor

Walterscheid, Jeffrey P.; Nghiem, Dat X.; Kazimi, Nasser; Nutt, Leta K.; McConkey, David J.; Norval, Mary; Ullrich, Stephen E.

doi:10.1073/pnas.0603119103

Cited by 155 publications

(134 citation statements)

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“…30 minutes before UVB, whereas control mice were injected with PBS alone. 17 A mixture of the antioxidants, vitamin E (0.05 mg; Sigma-Aldrich) and butylated hydroxytoluene (0.75 mg; Sigma-Aldrich), was injected i.p. 2 hours before UVB in olive oil (Sigma-Aldrich).…”

Section: Application Of Biological Modifiersmentioning

confidence: 99%

“…21 cis-UCA may mediate UVB-induced immunosuppression through the serotonin receptor. 17 On day 7 after immunization, mice were injected with SIINFEKL-CFSE-lo-and irrelevant-CFSE-hilabeled cells, and the extent of in vivo cytotoxic killing was determined from spleens at 4 hours after injection. Representative histograms from NoUV and UV-irradiated mice are shown.…”

Section: Cis-uca Can Inhibit Dth But Not Splenic Ova-specific Cd8 T-cmentioning

confidence: 99%

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Systemic Low-Dose UVB Inhibits CD8 T Cells and Skin Inflammation by Alternative and Novel Mechanisms

Rana

Rogers

Halliday

2011

The American Journal of Pathology

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Exposure to UVB radiation before antigen delivery at an unirradiated site inhibits functional immunological responses. Mice treated dorsally with suberythemal lowdose UVB and immunized with ova in abdominal skin generated ova-specific CD8 T cells with a significantly decreased activation, expansion, and cytotoxic activity compared with unirradiated mice. UVB also impaired the delayed-type hypersensitivity (DTH) reaction to ova. Transfer of CD4 ؉ CD25 ؉ cells from UVB-exposed mice did not suppress the ova-specific CD8 T-cell response or DTH reaction in unexposed mice, confirming that systemic low-dose UVB does not induce long-lived functional regulatory CD4 ؉ CD25 ؉ T cells. Repairing cyclobutane pyrimidine dimer-type DNA damage and blocking aryl hydrocarbon receptor signaling also did not reverse the immunosuppressive effect of UVB on ova-specific CD8 T cells and DTH, suggesting that cyclobutane pyrimidine dimers and the aryl hydrocarbon receptor are not required in systemic low-dose UVBinduced immunosuppression. The known UVB chromophore, cis-urocanic acid, and reactive oxygen species triggered the inhibition of DTH caused by UVB, but they were not involved in the modulation of CD8 T cells. These findings indicate that systemic low-dose UVB impedes the primary response of antigen-specific CD8 T cells by a novel mechanism that is independent of pathways known to be involved in systemic suppression of DTH. UVB radiation (290 to 320 nm) in natural sunlight is a potent immunosuppressant. UVB can inhibit the immune system from generating optimal responses to tumors, contact haptens, and various microbial antigens (Ags; viral, fungal, and parasitic) that can lead to exacerbated disease. Alternatively, immunosuppressive UVB can also be beneficial to control autoimmune diseases, such as psoriasis 1 and experimental autoimmune encephalomyelitis. 2 The epidermis of skin absorbs UVB through chromophores, including nuclear DNA, cytoplasmic tryptophan, and extracellular trans-urocanic acid (UCA). The molecular processes that follow trigger a cascade of events that cumulates in the phenomenon of UVB-induced immunosuppression. Some of the hallmarks of this immunosuppression include UVB-induced genetic mutations in skin cells, circulation of cis-UCA from the isomerization of trans-UCA, production of reactive oxygen species (ROS), and generation of regulatory T and B cells that can transfer suppression into UVB-naïve mice. 3 Because UVB has both detrimental and beneficial effects on the immune system, it is critical to understand the mechanisms regulated by UVB so that effective prophylactic and palliative therapies can be designed for skin diseases, such as skin cancer, and immune-mediated diseases in internal organs, such as multiple sclerosis.A previous study 4 showed that UVB can inhibit CD8 and CD4 T-cell responses to haptens. In a model of contact hypersensitivity (CHS), we demonstrated that a low dose of UVB (approximately 5 minutes of summer sunlight in Sydney, Australia, at midday) is sufficient to inhibit the activati...

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Section: Application Of Biological Modifiersmentioning

confidence: 99%

Section: Cis-uca Can Inhibit Dth But Not Splenic Ova-specific Cd8 T-cmentioning

confidence: 99%

Systemic Low-Dose UVB Inhibits CD8 T Cells and Skin Inflammation by Alternative and Novel Mechanisms

Rana

Rogers

Halliday

2011

The American Journal of Pathology

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“…This is perhaps not surprising when one considers the wide range of inflammatory mediators and cytokines that mast cells have been shown to produce (10). Indeed, many of the inflammatory mediators released by mast cells including, histamine (10,11), PGE 2 (12), serotonin (13), platelet-activating factor (PAF) (14,15) TNF, IL-4, and IL-10 (16) are critical mediators of UV-induced immunosuppression. Grimbaldeston et al (17) recently demonstrated that mast cell-derived IL-10 limits the skin pathology associated with contact dermatitis and chronic inflammation induced by UV exposure, again reinforcing the growing appreciation for the ability of mast cells to regulate inflammation and the immune response.…”

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confidence: 99%

Mast Cell Migration from the Skin to the Draining Lymph Nodes upon Ultraviolet Irradiation Represents a Key Step in the Induction of Immune Suppression

Byrne

Limón-Flores

Ullrich³

2008

The Journal of Immunology

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143

170

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The UV radiation in sunlight is the primary cause of skin cancer. UV is also immunosuppressive and numerous studies have shown that UV-induced immune suppression is a major risk factor for skin cancer induction. Previous studies demonstrated that dermal mast cells play a critical role in the induction of immune suppression. Mast cell-deficient mice are resistant to the immunosuppressive effects of UV radiation, and UV-induced immune suppression can be restored by injecting bone marrow-derived mast cells into the skin of mast cell- deficient mice. The exact process however, by which mast cells contribute to immune suppression, is not known. In this study, we show that one of the first steps in the induction of immune suppression is mast cell migration from the skin to the draining lymph nodes. UV exposure, in a dose-dependent manner, causes a significant increase in lymph node mast cell numbers. When GFP+ skin was grafted onto mast cell-deficient mice, we found that GFP+ mast cells preferentially migrated into the lymph nodes draining the skin. The mast cells migrated primarily to the B cell areas of the draining nodes. Mast cells express CXCR4+ and UV exposure up-regulated the expression of its ligand CXCL12 by lymph node B cells. Treating UV-irradiated mice with a CXCR4 antagonist blocked mast cell migration and abrogated UV-induced immune suppression. Our findings indicate that UV-induced mast cell migration to draining lymph nodes, mediated by CXCR4 interacting with CXCL12, represents a key early step in UV-induced immune suppression.

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“…29,32,33,35,37 Membrane phospholipids absorb UVR and lead to lipid peroxidation and transcription factor activation, favoring cytokine release and contributing to immunosuppression. 4,38,39 UVR exposure promotes oxidative stress, which induces not only DNA damage, but also the production of oxidized phospholipids, including platelet-activating factor (PAF). 35 PAF, secreted by keratinocytes almost immediately after UV exposure, is a lipid mediator of inflammation, being involved in photoimmunosuppression and photocarcinogenesis.…”

Section: Molecular Targetsmentioning

confidence: 99%

The dark side of the light: mechanisms of photocarcinogenesis

Coelho

Matos

Apetato

2016

Clinics in Dermatology

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Ultraviolet radiation (UVR) can have a beneficial biologic impact on skin, but it is also the most significant environmental risk factor for skin cancer development. Photocarcinogenesis comprises a complex interplay between the carcinogenic UVR, skin, and the immune system. UVB is absorbed by the superficial skin layers and is mainly responsible for direct DNA damage, which, if unrepaired, can lead to mutations in key cancer genes. UVA is less carcinogenic, penetrates deeper in the dermis, and mainly causes indirect oxidative damage to cellular DNA, proteins, and lipids, via photosensitized reactions. UVR not only induces mutagenesis, altering proliferation and differentiation of skin cells, but also has several immunosuppressive effects that compromise tumor immunosurveillance by impairing antigen presentation, inducing suppressive cells, and modulating the cytokine environment. This review focuses upon molecular and cellular effects of UVR, regarding its role in skin cancer development.

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Cis-urocanic acid, a sunlight-induced immunosuppressive factor, activates immune suppression via the 5-HT_2Areceptor

Cited by 155 publications

References 52 publications

Systemic Low-Dose UVB Inhibits CD8 T Cells and Skin Inflammation by Alternative and Novel Mechanisms

Systemic Low-Dose UVB Inhibits CD8 T Cells and Skin Inflammation by Alternative and Novel Mechanisms

Mast Cell Migration from the Skin to the Draining Lymph Nodes upon Ultraviolet Irradiation Represents a Key Step in the Induction of Immune Suppression

The dark side of the light: mechanisms of photocarcinogenesis

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Cis-urocanic acid, a sunlight-induced immunosuppressive factor, activates immune suppression via the 5-HT2Areceptor

Cited by 155 publications

References 52 publications

Systemic Low-Dose UVB Inhibits CD8 T Cells and Skin Inflammation by Alternative and Novel Mechanisms

Systemic Low-Dose UVB Inhibits CD8 T Cells and Skin Inflammation by Alternative and Novel Mechanisms

Mast Cell Migration from the Skin to the Draining Lymph Nodes upon Ultraviolet Irradiation Represents a Key Step in the Induction of Immune Suppression

The dark side of the light: mechanisms of photocarcinogenesis

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Cis-urocanic acid, a sunlight-induced immunosuppressive factor, activates immune suppression via the 5-HT_2Areceptor