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

Abstract

BackgroundPathogenic immune responses are known to play an important role in abdominal aortic aneurysm (AAA) development. Ultraviolet B (UVB) irradiation has been demonstrated to have therapeutic potential not only for cutaneous diseases but also for systemic inflammatory diseases in mice by suppressing immunoinflammatory responses. We investigated the effect of UVB irradiation on experimental AAA.Methods and ResultsWe used an angiotensin II–induced AAA model in apolipoprotein E–deficient mice fed a high‐cholesterol diet. Mice aged 10 weeks were irradiated with 5 kJ/m2 UVB once weekly for 6 weeks (UVB‐irradiated, n=38; nonirradiated, n=42) and were euthanized for evaluation of AAA formation at 16 weeks. Overall, 93% of angiotensin II–infused mice developed AAA, with 60% mortality possibly because of aneurysm rupture. UVB irradiation significantly decreased the incidence (66%) and mortality (29%) of AAA (P=0.004 and P=0.006, respectively). UVB‐irradiated mice had significantly smaller diameter AAA (P=0.008) and fewer inflammatory cells in the aortic aneurysm tissue than nonirradiated mice, along with systemic expansion of CD4+Foxp3+ regulatory T cells and decreased effector CD4+ CD44high CD62Llow T cells in para‐aortic lymph nodes. Genetic depletion of regulatory T cells abrogated these beneficial effects of UVB treatment, demonstrating a critical role of regulatory T cells.ConclusionsOur data suggest that UVB‐dependent expansion of regulatory T cells has beneficial effects on experimental AAA and may provide a novel strategy for the treatment of AAA.

Proenkephalin+regulatory T cells expanded by ultraviolet B exposure maintain skin homeostasis with a healing function

“…A well-known positive effect of UVB is immunosuppression. It is shown that UVB-induced immunosuppression is mediated by Treg cells in mouse models of contact hypersensitivity (44,45), experimental autoimmune encephalomyelitis, and atherosclerosis (46,47). UVB therapy is very effective for treatment of skin immunological disorders such as psoriasis and atopic dermatitis (48).…”

CTLA-4 Protects against Angiotensin II-Induced Abdominal Aortic Aneurysm Formation in Mice

“…A large body of experimental evidence indicates that the dysregulated balance between pro-inflammatory Teffs and anti-inflammatory Tregs contributes to the development and progression of AAA 4,5,11 and atherosclerotic disease 10,16,17 . Recent studies suggest that augmentation of the Treg/Teff ratio, by regulating Teff responses or promoting Treg responses, could be a feasible therapeutic approach for AAA 5,6 as well as atherosclerosis 18–20 . Our findings of attenuated Teff immune responses and AAA development mediated by CTLA-4 overexpression does not appear to be due to modulation of Treg responses, because angiotensin II-infused CTLA-4-Tg/ Apoe −/− mice had a markedly reduced number of CD4 + Foxp3 + Tregs compared with angiotensin II-infused Apoe −/− mice.…”

“…Previous experimental studies from several independent groups have demonstrated a protective role of forkhead box P3 (Foxp3)-expressing regulatory T cells (Tregs), which play an important role in dominant suppression of excessive immunoinflammatory reactions and maintenance of immune homeostasis 3 , in angiotensin II-induced experimental AAA 4,5 . Tipping the Treg/Teff balance toward Treg function by suppressing Teff responses and promoting Treg responses could be a feasible therapeutic approach for preventing AAA formation 5,6 .…”

Circulating Th1, Th2, Th9, Th17, Th22, and Treg Levels in Aortic Dissection Patients

“…Previous evidence demonstrated that increased Th1/IFN- γ , Th17/IL-17, and Th22/IL-22 resulted in elevated blood pressure, and uncontrolled hypertension was one of the main reasons for the presence of AD because higher than normal blood pressure can lead to the apoptosis of vascular SMCs. In recent studies, Hayashi et al reported that the downregulation induced by ultraviolet B irradiation significantly increased the rupture of angiotensin II-mediated aneurysms [ 39 ]. Honjo et al also found that an ApoB-100-related peptide vaccine protects against angiotensin II-induced aortic aneurysm formation and rupture via decreasing Th17/IL-17 expression [ 40 ].…”