UVB Exposure Prevents Atherosclerosis by Regulating Immunoinflammatory Responses

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.

[1]  K. Sakumi,et al.  Narrow-band UVB induces more carcinogenic skin tumors than broad-band UVB through the formation of cyclobutane pyrimidine dimer. , 2007, The Journal of investigative dermatology.

[2]  K. Hirata,et al.  Regulatory/effector T-cell ratio is reduced in coronary artery disease. , 2014, Circulation journal : official journal of the Japanese Circulation Society.

[3]  T. Nomura,et al.  CTLA-4 Control over Foxp3+ Regulatory T Cell Function , 2008, Science.

[4]  A. Voors,et al.  Altitude and arteriosclerotic heart disease mortality in white residents of 99 of the 100 largest cities in the United States. , 1979, Journal of chronic diseases.

[5]  M. Kasuga,et al.  Src Homology 2 Domain-Containing Protein Tyrosine Phosphatase Substrate 1 Regulates the Migration of Langerhans Cells from the Epidermis to Draining Lymph Nodes , 2004, The Journal of Immunology.

[6]  P. Libby,et al.  Progress and challenges in translating the biology of atherosclerosis , 2011, Nature.

[7]  M. Kripke,et al.  Origin and characteristics of ultraviolet-B radiation-induced suppressor T lymphocytes. , 1998, Journal of immunology.

[8]  S. Feldman,et al.  A review of phototherapy protocols for psoriasis treatment. , 2011, Journal of the American Academy of Dermatology.

[9]  G. Hansson,et al.  The immune system in atherosclerosis , 2011, Nature Immunology.

[10]  B. Hedblad,et al.  Low Levels of Circulating CD4+FoxP3+ T Cells Are Associated With an Increased Risk for Development of Myocardial Infarction But Not for Stroke , 2012, Arteriosclerosis, thrombosis, and vascular biology.

[11]  R. Daynes,et al.  Regulation of murine lymphokine production in vivo. Ultraviolet radiation exposure depresses IL-2 and enhances IL-4 production by T cells through an IL-1-dependent mechanism. , 1989, Journal of immunology.

[12]  T. Lüscher,et al.  Depletion of FOXP3+ regulatory T cells promotes hypercholesterolemia and atherosclerosis. , 2013, The Journal of clinical investigation.

[13]  K. Hirata,et al.  Regulatory T cells and tolerogenic dendritic cells as critical immune modulators in atherogenesis. , 2015, Current pharmaceutical design.

[14]  K. Hirata,et al.  CD3 Antibody and IL‐2 Complex Combination Therapy Inhibits Atherosclerosis by Augmenting a Regulatory Immune Response , 2014, Journal of the American Heart Association.

[15]  R. Flavell,et al.  Natural regulatory T cells control the development of atherosclerosis in mice , 2006, Nature Medicine.

[16]  D. Kaplan In vivo function of Langerhans cells and dermal dendritic cells. , 2010, Trends in immunology.

[17]  P. Perrin,et al.  Dynamics and function of Langerhans cells in vivo: dermal dendritic cells colonize lymph node areas distinct from slower migrating Langerhans cells. , 2005, Immunity.

[18]  R. Scragg Seasonality of cardiovascular disease mortality and the possible protective effect of ultra-violet radiation. , 1981, International journal of epidemiology.

[19]  B. Clausen,et al.  Langerhans cells are required for UVR-induced immunosuppression. , 2010, The Journal of investigative dermatology.

[20]  Ying Ma,et al.  Langerhans Cells Serve as Immunoregulatory Cells by Activating NKT Cells , 2010, The Journal of Immunology.

[21]  T. Nomura,et al.  Regulatory T Cells and Immune Tolerance , 2008, Cell.

[22]  NaotoSasaki,et al.  Oral Anti-CD3 Antibody Treatment Induces Regulatory T Cells and Inhibits the Development of Atherosclerosis in Mice , 2009 .

[23]  C. Bucana,et al.  Evidence that DNA damage triggers interleukin 10 cytokine production in UV-irradiated murine keratinocytes. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[24]  R. Takimoto,et al.  Narrowband ultraviolet B phototherapy ameliorates acute graft-versus-host disease by a mechanism involving in vivo expansion of CD4+CD25+Foxp3+ regulatory T cells , 2014, International Journal of Hematology.

[25]  J. Garssen,et al.  UV Exposure Alters Respiratory Allergic Responses in Mice¶ , 2000, Photochemistry and photobiology.

[26]  G. Stingl,et al.  Origin and Function of Epidermal Langerhans Cells , 1980, Immunological reviews.

[27]  Michael J. Pencina,et al.  Vitamin D Deficiency and Risk of Cardiovascular Disease , 2008, Circulation.

[28]  T. Schwarz Mechanisms of UV-induced immunosuppression. , 2005, The Keio journal of medicine.

[29]  K. Hogquist,et al.  Identification of a novel population of Langerin+ dendritic cells , 2007, The Journal of experimental medicine.

[30]  A. Shor,et al.  Sunlight, cholesterol and coronary heart disease. , 1997, QJM : monthly journal of the Association of Physicians.

[31]  M. Kripke Immunological Unresponsiveness Induced by Ultraviolet Radiation , 1984, Immunological reviews.

[32]  J. Penninger,et al.  Epidermal RANKL controls regulatory T-cell numbers via activation of dendritic cells , 2006, Nature Medicine.

[33]  K. Hirata,et al.  Oral Administration of an Active Form of Vitamin D3 (Calcitriol) Decreases Atherosclerosis in Mice by Inducing Regulatory T Cells and Immature Dendritic Cells With Tolerogenic Functions , 2010, Arteriosclerosis, thrombosis, and vascular biology.

[34]  Sungtae Kim,et al.  Multiple enhancer regions located at significant distances upstream of the transcriptional start site mediate RANKL gene expression in response to 1,25-dihydroxyvitamin D3 , 2007, The Journal of Steroid Biochemistry and Molecular Biology.

[35]  K. Hirata,et al.  Oral Anti-CD3 Antibody Treatment Induces Regulatory T Cells and Inhibits the Development of Atherosclerosis in Mice , 2009, Circulation.

[36]  S. Yamazaki,et al.  Photo(chemo)therapy Reduces Circulating Th17 Cells and Restores Circulating Regulatory T Cells in Psoriasis , 2013, PloS one.

[37]  J. Powell,et al.  Vitamin D and cardiovascular disease. , 2014, Circulation research.