Thymic Stromal Lymphopoietin Attenuates the Development of Atherosclerosis in ApoE ^−/− Mice

Abstract

BACKGROUND: Thymic stromal lymphopoietin (TSLP) is a cytokine with multiple effects on the body. For one thing, TSLP induces Th2 immunoreaction and facilitates allergic reaction; for another, it promotes the differentiation of naturally occurring CD4+CD25+Foxp3+ regulatory T cells (nTregs) and maintains immune tolerance. However, the exact role of TSLP in atherosclerosis remains unknown. METHODS AND RESULTS: In vitro, we examined the phenotype of TSLP-conditioned bone marrow dendritic cells (TSLP-DCs) of apolipoprotein E-deficient (ApoE-/-) mice and their capacity to induce the differentiation of Tregs. Our results indicated that TSLP-DCs obtained the characteristics of tolerogenic dendritic cells and increased a generation of CD4+ latency-associated peptide (LAP)+ Tregs and nTregs when cocultured with naive T cells. In addition, the functional relevance of TSLP and TSLP-DCs in the development of atherosclerosis was also determined. Interestingly, we found that TSLP was almost absent in cardiovascular tissue of ApoE-/- mice, and TSLP administration increased the levels of antioxidized low-density lipoprotein IgM and IgG1, but decreased the levels of IgG2a in plasma. Furthermore, mice treated with TSLP and TSLP-DCs developed significantly fewer (32.6% and 28.2%, respectively) atherosclerotic plaques in the aortic root compared with controls, along with increased numbers of CD4+LAP+ Tregs and nTregs in the spleen and decreased inflammation in the aorta, which could be abrogated by anti-TGF-β antibody. CONCLUSIONS: Our results revealed a protective role for TSLP in atherosclerosis that is possibly mediated by reestablishing a tolerogenic immune response, which may represent a novel possibility for treatment or prevention of atherosclerosis.