Abstract
BACKGROUND: Interleukin-23 (IL-23) has been implicated in inflammatory and autoimmune diseases by skewing CD4(+) T helper cells towards a pathogenic Th17 phenotype. In this study we investigated the presence of IL-23 receptor (IL-23R)-expressing cells in the atherosclerotic aorta and evaluated the effect of IL-23R deficiency on atherosclerosis development in mice. METHODS AND RESULTS: We used heterozygous Ldlr(-/-)Il23r(e)(GFP)(/)(WT) knock-in mice to identify IL-23R-expressing cells by flow cytometry and homozygous Ldlr(-/-)Il23r(e)(GFP)(/)(eGFP) (Ldlr(-/-)Il23r(-/-) ) mice to investigate the effect of lack of IL-23R in atherosclerosis. We demonstrate the presence of relatively rare IL-23R-expressing cells in lymphoid tissue and aorta (≈0.1-1% IL23R(+) cells of all CD45(+) leukocytes). After 10 weeks on a high-fat diet, production of IL-17, but not interferon-γ, by CD4(+) T cells and other lymphocytes was reduced in Ldlr(-/-)Il23r(-/-) compared with Ldlr(-/-) controls. However, Ldlr(-/-) and Ldlr(-/-)Il23r(-/-) mice had equivalent amounts of aortic sinus and descending aorta lesions. Adoptive transfer of IL-23R-deficient CD4(+) T cells to lymphopenic Ldlr(-/-)Rag1(-/-) resulted in dramatically reduced IL-17-producing T cells but did not reduce atherosclerosis, compared with transfer of IL-23R-sufficient CD4(+) T cells. CONCLUSIONS: These data demonstrate that loss of IL-23R does not affect development of experimental atherosclerosis in LDLr-deficient mice, despite a role for IL-23 in differentiation of IL-17-producing T cells.