Abstract 12763: Activation of Skin Dendritic Cells Controls Atherogensis in Mice
Background: Dermal Langerin+ dendritic cells (DCs) have been shown to play an important role in controlling not only skin inflammation but also systemic immune responses. Several studies have demonstrated that ultraviolet B (UVB) irradiation induces immunosuppression through modulating Langerin+ DC function. We examined the effects of dermal DC activation by UVB on atherosclerosis.
Methods and Results: Six-week-old apolipoprotein E-deficient (ApoE-/-) mice (n=10 per group) were UVB irradiated (5kJ/m2) once a week and atherosclerosis was assessed at 20 weeks old. UVB irradiation significantly increased 1,25(OH)2-dihydroxyvitamin D3 (VD) plasma levels by 1.9-fold (p≤0.05) and the proportion of Foxp3+ regulatory T cells (Tregs) exhibiting potent suppressor function in lymph nodes (LNs) by 20% (p≤0.05), along with suppression of systemic immune response and intraplaque inflammation, and reduced atherosclerosis development (aortic sinus plaque area: 1.84±0.20х105 vs. 2.94±0.31х105 μm2, p≤0.01) compared to controls. We found that UVB exposure triggered the migration of Langerin+ DCs from the skin to the draining LNs, where they might play a critical role in Treg induction. To elucidate the role of dermal DCs in the generation of Tregs and prevention of atherosclerosis by UVB, we developed langerin-diphtheria toxin receptor/ApoE-/- knock-in mice, allowing specific depletion of Langerin+ DCs by diphtheria toxin injection. Depletion of Langerin+ dermal DC resulted in a marked decrease in CD4+ T cell number but no change in the percentage of Foxp3+ Tregs in LNs, suggesting the important role for Langerin+ DCs in the maintenance of CD4+ T cell homeostasis under hypercholesterolemia, although it did not affect atherosclerosis development (3.70±0.41х105 vs. 3.22±0.28х105 μm2 in control and DC-depleted mice, respectively; n=7 to 9). In Langerin+ DC-depleted mice, UVB irradiation induced a 1.8-fold increase in VD levels, but had no effect on Treg number and atherosclerotic lesions (3.25±0.29х105 μm2; n=8), indicating the critical involvement of Langerin+ DCs, but not VD status, in the induction of Tregs and reduction of atherosclerosis.
Conclusions: Modulation of the skin immune system could be an attractivetherapeutic approach to atherosclerosis.
- © 2013 by American Heart Association, Inc.