Regulatory/Effector T-Cell Ratio Is Reduced in Coronary Artery Disease

Emoto, Takuo; Sasaki, Naoto; Yamashita, Tomoya; Kasahara, Kazuyuki; Yodoi, Keiko; Sasaki, Yoshihiro; Matsumoto, Takuya; Mizoguchi, Takahiro; Hirata, Ken‐ichi

doi:10.1253/circj.cj-14-0644

Cited by 49 publications

(33 citation statements)

References 22 publications

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“…All subjects provided oral and written informed con-(Tregs) 5,6) . We previously demonstrated that oral CD3 antibody or vitamin D3 can inhibit the progresion of atherosclerosis by increasing Tregs via modulating inetestinal immune system in mice 7,8) , and coronary artery disease (CAD) patients have reduced Treg and Treg/ Teff ratio compared with healthy controls 9) . Thus, we supposed that the composition of gut microbiota affects CAD 10) .…”

Section: Recruitment Of Patients and Volunteersmentioning

confidence: 99%

Analysis of Gut Microbiota in Coronary Artery Disease Patients: a Possible Link between Gut Microbiota and Coronary Artery Disease

Emoto

Yamashita

Sasaki

et al. 2016

J Atheroscler Thromb

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Section: Recruitment Of Patients and Volunteersmentioning

confidence: 99%

Analysis of Gut Microbiota in Coronary Artery Disease Patients: a Possible Link between Gut Microbiota and Coronary Artery Disease

Emoto

Yamashita

Sasaki

et al. 2016

J Atheroscler Thromb

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248

182

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“…7 There is also increasing clinical evidence showing the dysregulation of this balance in human coronary atherosclerotic disease. 8,9 It has long been known that UV irradiation critically affects the immune system. Numerous studies in the field of photoimmunology have reported that UV irradiation, in particular UVB, induces immunosuppression and dampens inflammatory reactions.…”

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confidence: 99%

UVB Exposure Prevents Atherosclerosis by Regulating Immunoinflammatory Responses

Sasaki

Yamashita

Kasahara

et al. 2017

ATVB

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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...

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“…[9][10][11] We and others have shown the contribution of reduced Treg levels to the progression of human coronary artery disease. 12,13 Recently, CD4 + CD25 + Treg deficiency caused by genetic disruption of CD80/CD86 or CD28 costimulatory molecules has been shown to promote the development and rupture of angiotensin II-induced AAA in C57BL/6 wild-type mice, 14 suggesting a crucial role for endogenous CD4 + CD25…”

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Foxp3 ⁺ Regulatory T Cells Play a Protective Role in Angiotensin II–Induced Aortic Aneurysm Formation in Mice

et al. 2015

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Although regulatory T cells (Tregs) have been shown to play a protective role in abdominal aortic aneurysm (AAA) formation, it remains unclear whether expansion of endogenous Foxp3 + Tregs prevents AAA. In the current study, we determined the effects of endogenous Foxp3 + Treg expansion or depletion in an experimental model of AAA. We continuously infused 12-week-old apolipoprotein E–deficient mice fed a high-cholesterol diet with angiotensin II (n=60) or normal saline (n=12) by implanting osmotic mini-pumps and evaluated AAA formation at 16 weeks. The angiotensin II–infused mice received interleukin-2/anti–interleukin-2 monoclonal antibody complex (interleukin-2 complex; n=31) or PBS (n=29). Eighty-one percent of angiotensin II–infused mice developed AAA, with 42% mortality possibly because of aneurysm rupture. Interleukin-2 complex treatment systemically increased the number of Foxp3 + Tregs and significantly decreased the incidence (52%) and mortality (17%) of AAA. Immunohistochemical analysis showed reduced accumulation of macrophages and increased numbers of Foxp3 + Tregs in aneurysmal tissues, suggesting that expansion of Tregs may suppress local inflammation in the vessel wall and provide protection against AAA formation. Furthermore, genetic depletion of Foxp3 + Tregs led to a significant increase in the mortality of AAA, suggesting the protective role of Foxp3 + Tregs against AAA. Our findings suggest that Foxp3 + Tregs may play a protective role in AAA formation and that promotion of an endogenous regulatory immune response may be a potentially valuable therapeutic approach for preventing AAA.

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Regulatory/Effector T-Cell Ratio Is Reduced in Coronary Artery Disease

Cited by 49 publications

References 22 publications

Analysis of Gut Microbiota in Coronary Artery Disease Patients: a Possible Link between Gut Microbiota and Coronary Artery Disease

Analysis of Gut Microbiota in Coronary Artery Disease Patients: a Possible Link between Gut Microbiota and Coronary Artery Disease

UVB Exposure Prevents Atherosclerosis by Regulating Immunoinflammatory Responses

Foxp3 ⁺ Regulatory T Cells Play a Protective Role in Angiotensin II–Induced Aortic Aneurysm Formation in Mice

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Regulatory/Effector T-Cell Ratio Is Reduced in Coronary Artery Disease

Cited by 49 publications

References 22 publications

Analysis of Gut Microbiota in Coronary Artery Disease Patients: a Possible Link between Gut Microbiota and Coronary Artery Disease

Analysis of Gut Microbiota in Coronary Artery Disease Patients: a Possible Link between Gut Microbiota and Coronary Artery Disease

UVB Exposure Prevents Atherosclerosis by Regulating Immunoinflammatory Responses

Foxp3 + Regulatory T Cells Play a Protective Role in Angiotensin II–Induced Aortic Aneurysm Formation in Mice

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Foxp3 ⁺ Regulatory T Cells Play a Protective Role in Angiotensin II–Induced Aortic Aneurysm Formation in Mice