UV-irradiated Mice Research Articles

Chronic ultraviolet irradiation induces memory deficits via dysregulation of the dopamine pathway

The effects of ultraviolet (UV) radiation on brain function have previously been investigated; however, the specific neurotransmitter-mediated mechanisms responsible for UV radiation-induced neurobehavioral changes remain elusive. In this study, we aimed to explore the mechanisms underlying UV radiation-induced neurobehavioral changes. In a mouse model, we observed that UV irradiation of the skin induces deficits in hippocampal memory, synaptic plasticity, and adult neurogenesis, as well as increased dopamine levels in the skin, adrenal glands, and brain. Chronic UV exposure altered the expression of genes involved in dopaminergic neuron differentiation. Furthermore, chronic peripheral dopamine treatments resulted in memory deficits. Systemic administration of a dopamine D1/D5 receptor antagonist reversed changes in memory, synaptic plasticity, adult neurogenesis, and gene expression in UV-irradiated mice. Our findings provide converging evidence that chronic UV exposure alters dopamine levels in the central nervous system and peripheral organs, including the skin, which may underlie the observed neurobehavioral shifts, such as hippocampal memory deficits and impaired neurogenesis. This study underscores the importance of protection from UV exposure and introduces the potential of pharmacological approaches targeting dopamine receptors to counteract the adverse neurological impacts of UV exposure.

UV Irradiation Increases Appetite and Prevents Body Weight Gain through the Upregulation of Norepinephrine in Mice

UV irradiation of the human skin downregulates lipid synthesis and adipokine production in subcutaneous fat. Recent evidence has suggested that UV exposure limits body weight gain in mouse models of obesity. However, the relationship between norepinephrine and UV irradiation has not been previously reported. Chronic UV exposure stimulated food intake but prevented body weight gain. Leptin, an appetite-suppressing hormone, was significantly reduced in the serum of the UV-irradiated mice. In contrast, UV irradiation induced browning of subcutaneous white adipose tissues without increasing physical activity. Notably, UV irradiation significantly increased norepinephrine levels, and the inhibition of norepinephrine production reversed the effects of chronic UV irradiation on food intake and body weight gain. In conclusion, chronic UV irradiation induces norepinephrine release, resulting in the stimulation of food intake due to the downregulation of leptin levels, but it prevents weight gain by inducing the browning process and elevating energy expenditure.

Topical Application of No-Ozone Cold Plasma in Combination with Vitamin C Reduced Skin Redness and Pigmentation of UV-Irradiated Mice.

Ultraviolet (UV) is the main cause of sunburn on the skin as it induces erythema and accelerates pigmentation. Vitamin C is one of the most frequently used compounds to reduce UV-induced skin pigmentation, but it has limitations in absorption through the skin. In this study, we tested whether a no-ozone cold plasma (NCP) treatment can improve UV-irradiated skin by helping the action of Vitamin C. For this, among five groups of HRM-2 hairless mice, four groups of mice were subjected to UVB irradiation, and three groups of UVB-treated mice were treated with NCP, Vitamin C, and NCP + Vitamin C, respectively. For evaluating the effect of each treatment, the melanin and erythema index was measured during animal experiments. Histological changes were monitored by performing H&E and MTS and IHC against tyrosinase and melanin. As a result, the naturally recovered mice showed a 28-point decrease in the melanin index, whereas a decrease of around 88, 74.3, and 106 points was detected in NCP-, Vitamin C-, and NCP + vitamin C-treated mice, respectively. Likewise, only a 39-point reduction in the erythema index was monitored in naturally recovered mice, but the NCP-, vitamin C-, and NCP + vitamin C-treated mice showed a 87.3-, 77-, and 111-point reduction, respectively. Interestingly, the skin tissues of the mice treated with NCP in combination with Vitamin C mostly recovered from UVB-induced damage. Altogether, this study elucidated the beneficial effect of the treatment of NCP in combination with Vitamin C on the UVB-irradiated skin, which might be helpful for treating sunburn on the skin.

Exposure to solar ultraviolet radiation establishes a novel immune suppressive lipidome in skin-draining lymph nodes.

The ability of ultraviolet radiation to suppress the immune system is thought to be central to both its beneficial (protection from autoimmunity) and detrimental (carcinogenic) effects. Previous work revealed a key role for lipids particularly platelet-activating factor and sphingosine-1-phosphate in mediating UV-induced immune suppression. We therefore hypothesized that there may be other UV-induced lipids that have immune regulatory roles. To assess this, mice were exposed to an immune suppressive dose of solar-simulated UV (8 J/cm2). Lipidomic analysis identified 6 lipids (2 acylcarnitines, 2 neutral lipids, and 2 phospholipids) with significantly increased levels in the skin-draining lymph nodes of UV-irradiated mice. Imaging mass spectrometry of the lipids in combination with imaging mass cytometry identification of lymph node cell subsets indicated a preferential location of UV-induced lipids to T cell areas. In vitro co-culture of skin-draining lymph node lipids with lymphocytes showed that lipids derived from UV-exposed mice have no effect on T cell activation but significantly inhibited T cell proliferation, indicating that the lipids play an immune regulatory role. These studies are important first steps in identifying novel lipids that contribute to UV-mediated immune suppression.

Protective effects of red orange (Citrus sinensis [L.] Osbeck [Rutaceae]) extract against UVA-B radiation-induced photoaging in Skh:HR-2 mice.

The skin is the outermost organ of the human body and plays a protective role against external environmental damages, such as sunlight and pollution, which affect anti-oxidant defenses and skin inflammation, resulting in erythema or skin reddening, immunosuppression, and epidermal DNA damage. The present study aimed to investigate the potential protective effects of red orange complex H extract (ROC) against ultraviolet (UV)-induced skin photoaging in Skh:HR-2 mice. ROC was orally administered at doses of 20, 40, and 80 mg/kg/day for 13 weeks, along with UV irradiation of the mice for 10 weeks. ROC improved UV-induced skin barrier parameters, including erythema, melanin production, transepidermal water loss, elasticity, and wrinkle formation. Notably, ROC inhibited the mRNA expression of pro-inflammatory cytokines (interleukin 6 and tumor necrosis factor α) and melanogenesis. In addition, ROC recovered the UV-induced decrease in the hyaluronic acid and collagen levels by enhancing genes expression. Furthermore, ROC significantly downregulated the protein and mRNA expression of matrix metalloproteinases responsible for collagen degradation. These protective effects of ROC against photoaging are associated with the suppression of UV-induced phosphorylation of c-Jun NH2-terminal kinase and activator protein 1 activation. Altogether, our findings suggest that the oral administration of ROC exerts potential protective activities against photoaging in UV-irradiated hairless mice.

Abstract A021: Development of a novel MEK inhibitor, NFX-179, as a chemoprevention agent for squamous cell carcinoma

Abstract Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer comprising at least 20% of all non-melanoma skin cancers. While cSCC contributes to significant morbidity and mortality in high-risk individuals, deployment of otherwise effective chemoprevention of cSCC is limited by toxicities. To help address this, we conducted a systematic computational drug repositioning screen which predicted that selumetinib, an FDA-approved MEK inhibitor (MEKi), would reverse transcriptional signatures associated with cSCC development. This is consistent with our genomic analysis implicating ETS2, a transcription factor in the canonical RAS/RAF/MEK/ERK Mitogen-Activated Protein Kinase (MAPK) pathway, as an upstream regulator of cSCC development. Therefore, as a key regulator of the MAPK pathway, we reasoned MEK would be a viable chemopreventive target. Although systemic MEK inhibition suppresses the formation of cSCC in mice, systemic MEKi administration causes significant adverse effects, including diarrhea, peripheral edema, cardiomyopathy and retinal toxicity. Here, we report the development of a topically formulated, metabolically labile, novel MEKi, NFX-179, designed to potently and selectively suppress the MAPK pathway in the skin prior to rapid metabolism in the systemic circulation. NFX-179 was identified from a targeted drug discovery effort based on its biochemical and cellular potency, selectivity, and rapid metabolism upon systemic absorption. In our UV-induced cSCC mouse model, topical application of NFX- 179 gel reduced the formation of new cSCCs by an average of 60% at doses of 0.1% and greater at 28 days. No systemic or skin toxicities were observed in this model. Furthermore, we conducted a second split-mouse randomized controlled study in which NFX-179 0.5% gel was applied to one half of the back and vehicle was applied to the opposite half of each of the UV-irradiated mice. Near complete suppression of cSCC was observed only in the drug-treated area, demonstrating the targeted and dermal effect of the intervention. NFX-179 inhibits the growth of human SCC cell lines in a dose-dependent manner and topical NFX-179 application penetrates human skin and inhibits MAPK signaling in human cSCC explants. Together our data provide compelling rationale for using topical MEK inhibition through application of NFX-179 gel as an effective strategy for cSCC chemoprevention. Citation Format: Kavita Y. Sarin, John Kincaid, Brittney Sell, Jahanbanoo Shahryari, Matthew A. J. Duncton, Elaine Morefield, Wenchao Sun, Omar Chavez-Chiang, Scott R. Plotkin, Gerd G. Kochendoerfer, Peter Fenn, Christopher Powala, Kenneth Y. Tsai. Development of a novel MEK inhibitor, NFX-179, as a chemoprevention agent for squamous cell carcinoma [abstract]. In: Proceedings of the Second Biennial NCI Meeting: Translational Advances in Cancer Prevention Agent Development (TACPAD); 2022 Sep 7-9. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_2): Abstract nr A021.

Explore the multitarget mechanism of tetrahydrocurcumin preventing on UV-induced photoaging mouse skin

UV induced photoaging is the main external factor of skin aging. In this study, we tested the protective effects of tetrahydrocurcumin on UV-induced skin photoaging of KM mice and researched the multi-target mechanism through RNA sequencing technology. Mouse experiments show that tetrahydrocurcumin strongly changed in skin appearance, epidermal thickness, and wrinkle-related parameters in UV-irradiated mice. RNA-seq result show that we found 29 differentially expressed mRNA transcripts in UV mice relative to Ctrl rats (18 up-regulated and 11 down-regulated) and 7 significantly dysregulated mRNAs were obtained in the THC group compared to the UV group (1 up-regulated and 6 down-regulated), respectively. Spink7, Edn3, Stab2 may be the key target genes of tetrahydrocurcumin in preventing aging. Bioinformatics analysis shows that the response to muscle contraction and melanin biosynthetic GO term and Inflammation related pathway such as PPAR, MAPK would involve in effects of tetrahydrocurcumin. The results of this study indicated that tetrahydrocurcumin can improve the appearance through anti-inflammatory, improving extracellular matrix and inhibiting melanin production. It could be suggested as a protective measure in the prevention of UV-induced photoaging.

Protective Effect of the Pearl Extract from Pinctada fucata martensii Dunker on UV‐Induced Photoaging in Mice

Although the effect of pearl powder has been recognized for more than a thousand years from healthcare to beauty care, there has yet to be an in-depth understanding of its anti-photoaging effect. In the present study, the protective effect of pearl extract (PE) on UV-induced photoaging in mice was evaluated. First, the amino acid analysis of PE was carried out. Then, different dosages of pearl extract gel (PEG) were applied topically on the shaved dorsal skins regions of mice before UV irradiation. Skin physiological and histological analysis, antioxidant enzymes and inflammatory factor test were used to evaluate the anti-photoaging effect of PEG. The results showed that PEG contained 14 amino acids, and could inhibit UV-irritated skin wrinkles, laxity, thickness, and dryness. Moreover, PEG upregulated the activities of CAT, GSH-Px, SOD and decreased MDA level, and suppressed the production of IL-1β, IL-6, PGE2 , TNF-α, and COX-2 in UV-irradiated mice. The therapeutic effect in high dose PEG group was superior to those of positive control (Vitamin E). This study demonstrated the underlying mechanisms of PEG against UV-irritated photoaging. And PEG possesses a potential use in photoprotective medicines and cosmetics.

Improvement of Skin Barrier Dysfunction by Phenolic‐containing Extracts of Lycium barbarum via Nrf2/HO‐1 Regulation

Lycium barbarum have received an increasing popularity due to its powerful biological activity and medicinal use. However, the effect of Lycium barbarum on skin remains largely uncharacterized. The general purpose of this paper was to characterize the phenolic compounds in Lycium barbarum extract (LBE) using LC-HRMS/QTOF method and to investigate whether topical administration of LBE can repair skin barrier dysfunction in mice. Our data demonstrated that LBE could not only decrease ROS level and matrix metalloproteinase expression, but also strengthen intrinsic antioxidant defense system including SOD, GSH-Px and CAT, thereby resulting in increased skin collagen content and an improvement of UV-induced skin erythema, thickness and wrinkles. Improved skin barrier functions were highly correlated with increased expression of filaggrin, involucrin and loricrin as well as antioxidant proteins such as Nrf2 and HO-1 in UV-irradiated mice, suggesting that LBE may be promising natural products at a lower cost for the topical application in the treatment of skin diseases with defective barrier function.

Chronic Ultraviolet Irradiation to the Skin Dysregulates Adrenal Medulla and Dopamine Metabolism In Vivo.

Ultraviolet (UV) radiation has a strong biological effect on skin biology, and it switches on adaptive mechanisms to maintain homeostasis in organs such as the skin, adrenal glands, and brain. In this study, we examined the adaptation of the body to repeated bouts of UVB radiation, especially with respect to the catecholamine synthesis pathway of the adrenal glands. The effects of UVB on catecholamine-related enzymes were determined by neurochemical and histological analyses. To evaluate catecholamine changes after chronic excessive UVB irradiation of mouse skin, we examined dopamine and norepinephrine levels in the adrenal glands and blood from UV-irradiated and sham-irradiated mice. We found that chronic excessive UVB exposure significantly reduced dopamine levels in both tissues but did not affect norepinephrine levels. In addition, UVB irradiation significantly increased the levels of related enzymes tyrosine hydroxylase and dopamine-β-hydroxylase. Furthermore, we also found that apoptosis-associated markers were increased and that oxidative defense proteins were decreased, which might have contributed to the marked structural abnormalities in the adrenal medullas of the chronically UVB-irradiated mice. This is the first evidence of the damage to the adrenal gland and subsequent dysregulation of catecholamine metabolism induced by chronic exposure to UVB.

487 Topical MEK inhibition as precision targeted chemoprevention

Cutaneous squamous cell carcinoma (cuSCC) comprises at least 20% of all non-melanoma skin cancers. Effective chemoprevention for cuSCC is lacking and high-risk cuSCC causes significant surgical morbidity. Previously, we conducted RNA-seq analysis of human cuSCC, which identified ETS2, a transcription factor in the ERK pathway, as an upstream regulator of cuSCC development. Consistent with this, our computational drug repositioning screen predicted the FDA-approved MEK1, 2 inhibitor, selumetinib, as a therapeutic for cuSCC based on its ability to reverse transcriptional signatures associated with cuSCC development. As a regulator of ERK activity, we reasoned MEK would be a viable chemopreventative target. Although systemic MEK inhibition suppresses tumor formation, systemic MEKi administration causes significant adverse effects. Here, we report the development of a topically formulated, metabolically labile MEK inhibitor, NFX-179, designed to potently and selectively suppress the ERK pathway in the skin prior to rapid degradation in the circulation. In our UV-induced model of cuSCC, topical application of NFX-179 gel reduced the formation of new cuSCCs by an average of 60% at doses of 0.1% and greater at 28 days. No systemic or skin toxicities were observed. Furthermore, we conducted a split-mouse randomized controlled study in 5 mice. NFX-179 0.5% gel was applied to half of the back and vehicle was applied to the other half of each of the UV-irradiated mice. Near complete suppression of cuSCC was observed only in the drug-treated area, demonstrating the targeted and local effect of the intervention. NFX-179 inhibits the growth of human cSCC cell lines in a dose-dependent manner and topical NFX-179 application penetrates human skin and inhibits ERK signaling in human cuSCC explants. Our data provide compelling evidence that topical application of NFX-179 is a safe, effective strategy for SCC chemoprevention in high risk individuals.

Short-range UV-LED irradiation in postmenopausal osteoporosis using ovariectomized mice

Postmenopausal osteoporosis is crucial condition that reduces the QOL of affected patients just like aged type osteoporosis. The aim of this study was to evaluate the effectiveness of short-range UV-LED irradiation in postmenopausal osteoporosis using ovariectomized mice. Preliminary experiments identified the time of onset of osteoporosis after ovariectomy (8 weeks) in our model. We have set up a total of 4 groups (n = 8/group); vitamin D-repletion with UV irradiation (Vit.D+UV+), vitamin D-repletion without UV irradiation (Vit.D+UV−), vitamin D-deficiency with UV irradiation (Vit.D-UV+), vitamin D-deficiency without UV irradiation (Vit.D-UV−), and. From 8 weeks after ovariectomy, UV was irradiated for 24 weeks. At the time of 16 and 24 weeks’ irradiation, serum Vit.D levels, various markers of bone metabolism, bone mineral density, and bone strength were evaluated, and histological analyses were performed. In addition, muscle strength was analyzed. Serum 25-hydroxyvitamin D [25 (OH) D] levels at 40 and 48 weeks of age were increased in the Vit.D-UV+ group compared to the Vit.D-UV−group. Cortical thickness evaluated with micro-CT and strength of bone were significantly higher in Vit.D-UV+ group than those in Vit.D-UV− group. There was no difference in muscle strength between Vit.D-UV+ group and Vit.D-UV− group. No obvious adverse effects were observed in UV-irradiated mice including skin findings. Short-range UV irradiation may ameliorate postmenopausal osteoporosis associated with a state of vitamin D deficiency.

MSC-derived exosomes protect against oxidative stress-induced skin injury via adaptive regulation of the NRF2 defense system

Oxidative stress is a major cause of skin injury induced by damaging stimuli such as UV radiation. Currently, owing to their immunomodulatory properties, mesenchymal stem cell-derived exosomes (MSC-Exo), as a nanotherapeutic agent, have attracted considerable attention. Here, we investigated the therapeutic effects of MSC-Exo on oxidative injury in H2O2-stimulated epidermal keratinocytes and UV-irradiated wild type and nuclear factor-erythroid 2-related factor-2 (Nrf2) knocked down cell and animal models. Our findings showed that MSC-Exo treatment reduced reactive oxygen species generation, DNA damage, aberrant calcium signaling, and mitochondrial changes in H2O2-stimulated keratinocytes or UV-irradiated mice skin. Exosome therapy also improved antioxidant capacities shown by increased ferric ion reducing antioxidant power and glutathione peroxidase or superoxide dismutase activities in oxidative stress-induced cell and skin injury. In addition, it alleviated cellular and histological responses to inflammation and oxidation in cell or animal models. Furthermore, the NRF2 signaling pathway was involved in the antioxidation activity of MSC-Exo, while Nrf2 knockdown attenuated the antioxidant capacities of MSC-Exo in vitro and in vivo, suggesting that these effects are partially mediated by the NRF2 signaling pathway. These results indicate that MSC-Exo can repair oxidative stress-induced skin injury via adaptive regulation of the NRF2 defense system. Thus, MSC-Exo may be used as a potential dermatological nanotherapeutic agent for treating oxidative stress-induced skin diseases or disorders.

155 A biomarker function of HMGA2 in cutaneous squamous cell carcinoma development

The high mobility group AT-hook 2 (HMGA2) gene encodes a transcription factor that is expressed during embryonic development but down-regulated in adult tissues. Re-expression of HMGA2 in adult tissues is often associated with both benign and malignant tumor formation. HMGA2 has been identified as a biomarker of melanoma progression and prognosis, but its role in non-melanoma skin cancer development remains controversial. In this study, we measured HMGA2 expression in normal human keratinocytes and found a significant decrease in HMGA2 mRNA expression in adult keratinocytes compared to neonatal keratinocytes. HMGA2 is highly expressed in human cutaneous squamous cell carcinoma (SCC) cell lines and primary human SCC tumors, but not detected in adjacent normal skin. In mouse skin, Hmga2 has been found to be translocated from the cell membrane into the nucleus during DMBA/TPA-induced skin tumorigenesis. While Hmga2 expression is absent in the hair follicle in non-UV-irradiated mouse, UV irradiation increased Hmga2 expression in both the epidermis and hair follicles. In agreement, we found enhanced Hmga2 expression in UV-induced mouse skin SCCs and also Hmga2 reactivation in the dermis from UV-irradiated mice. Furthermore, oncogene depletion such as FOXM1 and TRIP13 in human SCC cell lines using CRISPR/Cas9 decreased the expression of HMGA2 coupled with decreased cell proliferation and survival. Taken together, these results demonstrate that the upregulation of HMGA2 is an important biomarker of skin SCC tumorigenesis. Moreover, understanding of the mechanism for HMGA2 overexpression in skin hair follicle cells can develop the new drug for skin cancer treatment.

Effect of lemon peel flavonoids on UVB-induced skin damage in mice.

By establishing an effective ultraviolet B (UVB) radiation model of skin damage in mice, the effect of lemon peel flavonoids (LPF) on skin damage was explored. UVB skin damage in UV-irradiated mice was simulated, and animal models were established. Serum parameters were measured using kits, skin sections were stained with hematoxylin–eosin (H&E) and Masson, and quantitative polymerase chain reaction (qPCR) was used to detect the expression of skin tissue-related mRNA. The experimental results showed that LPF increased the activity of catalase (CAT) and superoxide dismutase (SOD) oxidases in serum of mice with UVB-induced skin damage and decreased MDA, interleukin-1β (IL-1β), IL-6, IL-10, and tumor necrosis factor-alpha (TNF-α) levels. Pathological observation indicated that LPF alleviated the skin tissue lesions caused by UVB. LPF upregulated the mRNA expression of SOD1, SOD2, CAT, nuclear factor erythroid-2 related factor 2 (Nrf2), heme oxygenase-1 (HO-1), and inhibitor of NF-κB alpha (IκB-α) and downregulated the expression of nuclear factor kappa B (NF-κB), p38 MAPK, and cyclooxygenase-2 (COX-2) in the skin tissue of skin-damaged mice. There was a greater protective effect of LPF on the skin as compared to vitamin C (VC) at the same application concentration, and the effect of LPF was positively correlated with the concentration. High performance liquid chromatography (HPLC) analysis showed that LPF contained five flavonoid compounds, namely isomangiferin, rutin, astragalin, naringin, and quercetin. We demonstrated that flavonoids from LPF exhibit an excellent skin protection effect with satisfactory application value.

Topical treatment with a cathepsin G inhibitor, β-keto-phosphonic acid, blocks ultraviolet irradiation-induced basement membrane damage in hairless mouse skin.

Ultraviolet light (UV) exposure contributes various effects to skin including damage of the basement membrane. Cathepsin G (CTSG) belongs to serine protease family, and its upregulation is involved in wrinkle formation by chronic UV irradiation. However, the effect of CTSG on the basement membrane damage in skin remains unclear. To investigate the effects of topical treatment with a CTSG inhibitor, β-keto-phosphonic acid (KPA), on basement membrane damage in chronically UV-irradiated hairless mouse skin. The dorsal skin of hairless mice was exposed to UV three times per week for 8weeks. KPA was applied immediately after each session of UV irradiation. The basement membrane components, CTSG expression, and neutrophil infiltration were analyzed by immunofluorescence staining. The basement membrane structures were visualized by transmission electron microscope. CTSG and MMP-13 protein levels were analyzed by Western blotting. Assessment of wrinkle formation was examined using a skin replica assay. β-keto-phosphonic acid prevented UV irradiation-induced decrease in type VII collagen, laminin 332, and perlecan at the basement membrane zone and prevented UV-induced breakage of lamina densa and UV-induced shortening of hemidesmosome. KPA prevented UV-induced CTSG and MMP-13 expressions in chronically UV-irradiated hairless mice. Increase in neutrophil infiltration by UV irradiation and UV-induced wrinkle formation was also prevented by KPA. Our present study showed the possible involvement of CTSG in UV-induced basement membrane damage in skin through topical treatment with a CTSG inhibitor, KPA. Thus, inhibition of CTSG may be a useful strategy for the prevention of UV-induced basement membrane damage and photoaging.

Ultraviolet Irradiation of Skin Alters the Faecal Microbiome Independently of Vitamin D in Mice.

Reduced sunlight exposure has been associated with an increased incidence of Crohn’s disease and ulcerative colitis. The effect of ultraviolet radiation (UVR) on the faecal microbiome and susceptibility to colitis has not been explored. C57Bl/6 female mice were fed three different vitamin D-containing diets for 24 days before half of the mice in each group were UV-irradiated (1 kJ/m2) for each of four days, followed by twice-weekly irradiation of shaved dorsal skin for 35 days. Faecal DNA was extracted and high-throughput sequencing of the 16S RNA gene performed. UV irradiation of skin was associated with a significant change in the beta-diversity of faeces compared to nonirradiated mice, independently of vitamin D. Specifically, members of phylum Firmicutes, including Coprococcus, were enriched, whereas members of phylum Bacteroidetes, such as Bacteroidales, were depleted. Expression of colonic CYP27B1 increased by four-fold and IL1β decreased by five-fold, suggesting a UVR-induced anti-inflammatory effect. UV-irradiated mice, however, were not protected against colitis induced by dextran sodium sulfate (DSS), although distinct faecal microbiome differences were documented post-DSS between UV-irradiated and nonirradiated mice. Thus, skin exposure to UVR alters the faecal microbiome, and further investigations to explore the implications of this in health and disease are warranted.

Reticulon-1 and Reduced Migration toward Chemoattractants by Macrophages Differentiated from the Bone Marrow of Ultraviolet-Irradiated and Ultraviolet-Chimeric Mice.

The ability of macrophages to respond to chemoattractants and inflammatory signals is important for their migration to sites of inflammation and immune activity and for host responses to infection. Macrophages differentiated from the bone marrow (BM) of UV-irradiated mice, even after activation with LPS, migrated inefficiently toward CSF-1 and CCL2. When BM cells were harvested from UV-irradiated mice and transplanted into naive mice, the recipient mice (UV-chimeric) had reduced accumulation of elicited monocytes/macrophages in the peritoneal cavity in response to inflammatory thioglycollate or alum. Macrophages differentiating from the BM of UV-chimeric mice also had an inherent reduced ability to migrate toward chemoattractants in vitro, even after LPS activation. Microarray analysis identified reduced reticulon-1 mRNA expressed in macrophages differentiated from the BM of UV-chimeric mice. By using an anti-reticulon-1 Ab, a role for reticulon-1 in macrophage migration toward both CSF-1 and CCL2 was confirmed. Reticulon-1 subcellular localization to the periphery after exposure to CSF-1 for 2.5 min was shown by immunofluorescence microscopy. The proposal that reduced reticulon-1 is responsible for the poor inherent ability of macrophages to respond to chemokine gradients was supported by Western blotting. In summary, skin exposure to erythemal UV radiation can modulate macrophage progenitors in the BM such that their differentiated progeny respond inefficiently to signals to accumulate at sites of inflammation and immunity.

Red tattoos, ultraviolet radiation and skin cancer in mice.

Ultraviolet radiation (UVR) induces skin cancer. The combination of UVR and red tattoos may be associated with increased risk of skin cancer due to potential carcinogens in tattoo inks. This combination has not been studied previously. Immunocompetent C3.Cg/TifBomTac hairless mice (n=99) were tattooed on their back with a popular red tattoo ink. This often used ink is banned for use on humans because of high content of the potential carcinogen 2-anisidine. Half of the mice were irradiated with three standard erythema doses UVR thrice weekly. Time to induction of first, second and third squamous cell carcinoma (SCC) was measured. All UV-irradiated mice developed SCCs. The time to the onset of the first and second tumor was identical in the red-tattooed group compared with the control group (182 vs 186days and 196 vs 203days, P=ns). Statistically, the third tumor appeared slightly faster in the red-tattooed group than in the controls (214 vs 224days, P=.043). For the second and third tumor, the growth rate was faster in the red-tattooed group compared with the control (31 vs 49days, P=.009 and 30 vs 38days, P=.036). In conclusion, no spontaneous cancers were observed in skin tattooed with a red ink containing 2-anisidine. However, red tattoos exposed to UVR showed faster tumor onset regarding the third tumor, and faster growth rate of the second and third tumor indicating red ink acts as a cocarcinogen with UVR. The cocarcinogenic effect was weak and may not be clinically relevant.

UV Irradiation of Skin Enhances Glycolytic Flux and Reduces Migration Capabilities in Bone Marrow–Differentiated Dendritic Cells

A systemic immunosuppression follows UV irradiation of the skin of humans and mice. In this study, dendritic cells (DCs) differentiating from the bone marrow (BM) of UV-irradiated mice had a reduced ability to migrate toward the chemokine (C-C motif) ligand 21. Fewer DCs also accumulated in the peritoneal cavity of UV-chimeric mice (ie, mice transplanted with BM from UV-irradiated mice) after injection of an inflammatory stimulus into that site. We hypothesized that different metabolic states underpin altered DC motility. Compared with DCs from the BM of nonirradiated mice, those from UV-irradiated mice produced more lactate, consumed more glucose, and had greater glycolytic flux in a bioenergetics stress test. Greater expression of 3-hydroxyanthranilate 3,4-dioxygenase was identified as a potential contributor to increased glycolysis. Inhibition of 3-hydroxyanthranilate 3,4-dioxygenase by 6-chloro-dl-tryptophan prevented both increased lactate production and reduced migration toward chemokine (C-C motif) ligand 21 by DCs differentiated from BM of UV-irradiated mice. UV-induced prostaglandin E2 has been implicated as an intermediary in the effects of UV radiation on BM cells. DCs differentiating from BM cells pulsed invitro for 2 hours with dimethyl prostaglandin E2 were functionally similar to those from the BM of UV-irradiated mice. Reduced migration of DCs to lymph nodes associated with increased glycolytic flux may contribute to their reduced ability to initiate new immune responses in UV-irradiated mice.