UVB Exposure Prevents Atherosclerosis by Regulating Immunoinflammatory Responses

Abstract

Objective-UVB irradiation is an established treatment for immunoinflammatory cutaneous disorders and has been shown to suppress cutaneous and systemic inflammatory diseases through modulation of the adaptive immune response. However, it remains unknown whether UVB irradiation prevents an immunoinflammatory disease of arteries such as atherosclerosis. Approach and Results-Here, we show that UVB exposure inhibits the development and progression of atherosclerosis in atherosclerosis-prone mice by expanding and enhancing the functional capacity of CD4 + forkhead box P3 + regulatory T cells and regulating proatherogenic T-cell responses. Experimental studies in Langerhans cell-depleted mice revealed that epidermal Langerhans cells play a critical role in UVB-dependent induction of CD4 + forkhead box P3 + regulatory T cells, suppression of proatherogenic T-cell responses, and prevention of atherosclerotic plaque development. Conclusions-Our findings suggest the skin immune system as a novel therapeutic target for atherosclerosis and provide a novel strategy for the treatment and prevention of atherosclerosis. Correspondence to Naoto Sasaki, MD, PhD, Department of Medical Pharmaceutics, Kobe Pharmaceutical University, 4-19-1, Motoyamakita-machi, Higashinada-ku, Kobe, 658-8558, Japan. E-mail n-sasaki@kobepharma-u.ac.jp; or Tomoya Yamashita, MD, PhD, Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. E-mail tomoya@ med.kobe-u.ac.jp Despite advances in our understanding of the chronic immunoinflammatory nature of atherosclerosis, therapeutics aimed to intervene inflammation or immune system remains to be implemented in clinical practice. UVB-based phototherapy is the firstline treatment for immunoinflammatory cutaneous disorders such as psoriasis in humans without serious side effects. 15 Here, we investigated the effect of UVB irradiation on atherosclerosis and its underlying mechanisms in hypercholesterolemic mice. Our findings provide first evidence that UVB exposure inhibits the development and progression of atherosclerosis. Using hypercholesterolemic LC-depleted mice, we clearly demonstrated that epidermal LCs play a critical role in UVB-dependent induction of CD4 + UVB Exposure Prevents Atherosclerosis by Regulating Immunoinflammatory Responses Foxp3+ Tregs, suppression of proatherogenic T-cell responses, and prevention of atherosclerotic plaque development. Our data suggest that UVB-based modulation of the skin immune system for inducing atheroprotective Tregs may be an attractive approach to treat and prevent atherosclerosis. Materials and MethodsMaterials and Methods are available in the online-only Data Supplement. Results UVB Irradiation Inhibits the Initiation and Progression of Atherosclerotic Plaque Formation in Atherosclerotic MiceTo study the effect of UVB irradiation on the development of atherosclerosis, apolipoprotein E-deficient (Apoe −/− ) mice were irradiated with 2 or 5 kJ/m 2 UVB on...

Ultraviolet B Exposure Inhibits Angiotensin II–Induced Abdominal Aortic Aneurysm Formation in Mice by Expanding CD4 + Foxp3 + Regulatory T Cells

“…These reports raise the possibility that UVB‐dependent promotion of cutaneous synthesis of vitamin D may be responsible for attenuation of AAA formation in the present study. Whereas our recent work showed a significant increase in biologically active 1,25‐dihydroxyvitamin D plasma levels in UVB‐irradiated Apoe −/− mice without angiotensin II infusion, we found no changes in its plasma levels in the present study in UVB‐irradiated Apoe −/− mice treated with angiotensin II, excluding a substantial contribution of vitamin D to the protective effects of UVB irradiation in our AAA model. Angiotensin II is reported to downregulate renal Klotho expression, which leads to increased levels of fibroblast growth factor 23; subsequent suppression of 1α‐hydroxylase, known to convert circulating storage form 25‐hydroxyvitamin D to highly active 1,25‐dihydroxyvitamin D; and reduced production of 1,25‐dihydroxyvitamin D in the kidney .…”

“…At 7 days after pump implantation and 4 days after the last UVB irradiation, lymphoid cells from skin‐draining LNs and spleen were prepared and analyzed by flow cytometry. Consistent with our previous report using Apoe −/− mice without angiotensin II infusion, UVB irradiation significantly increased the frequency of CD4 + Foxp3 + Tregs in the skin‐draining LNs of angiotensin II–infused mice (Figure A). Moreover, an increase in frequency of CD4 + Foxp3 + Tregs was also observed in the spleen of UVB‐irradiated mice (Figure A).…”

“…Angiotensin II is reported to downregulate renal Klotho expression, which leads to increased levels of fibroblast growth factor 23; subsequent suppression of 1α‐hydroxylase, known to convert circulating storage form 25‐hydroxyvitamin D to highly active 1,25‐dihydroxyvitamin D; and reduced production of 1,25‐dihydroxyvitamin D in the kidney . Consequently, we speculate that the inconsistency in plasma 1,25‐dihydroxyvitamin D levels between the present study and previous work may be due to downregulation of renal Klotho expression in this angiotensin II–induced AAA model. We propose a novel vitamin D–independent mechanism for UVB‐dependent prevention of AAA, attributed to the modification of the immune system.…”

“…UVB irradiation has been shown to suppress cutaneous and systemic inflammatory diseases by modulating Teff immune responses, which may vary depending on the disease models used . We recently investigated the effect of UVB irradiation on atherosclerosis in hypercholesterolemic mice and demonstrated that UVB exposure prevents atherosclerosis by expanding activated CD4 + Foxp3 + Tregs and by suppressing pathogenic immune responses . Importantly, in clinical settings, immunoinflammatory cutaneous disorders such as psoriasis are treated with UVB without any serious side effects.…”

Anti-Inflammatory Role of Langerhans Cells and Apoptotic Keratinocytes in Ultraviolet-B–Induced Cutaneous Inflammation

“…In vivo experiments using Cytochalasin D demonstrated that an anti-inflammatory effect mediated by phagocytosis was observed in UVB-induced cutaneous inflammation, and the presence of LCs is partially required for this anti-inflammatory response. We (8,33) and other investigators (9) already reported that LCs can migrate to draining lymph nodes after UVB irradiation where they activate NKT cells and CD4 + Foxp3 + regulatory T cells. This suggests that LCs may phagocytose UV-induced apoptotic keratinocytes, such as sunburn cells in vivo, migrate to regional lymph nodes, and prime regulatory cell expansion in draining lymph nodes, leading to the regulation of sunburn-induced inflammation.…”