1. Transforming growth factor-β signaling in T cells promotes stabilization of atherosclerotic plaques through an interleukin-17-dependent pathway.
- Author
-
Gisterå A, Robertson AK, Andersson J, Ketelhuth DF, Ovchinnikova O, Nilsson SK, Lundberg AM, Li MO, Flavell RA, and Hansson GK
- Subjects
- Animals, Antibodies, Neutralizing pharmacology, Aorta pathology, Bone Marrow Cells drug effects, Bone Marrow Cells pathology, Chimera, Collagen biosynthesis, Humans, Immunohistochemistry, Integrases metabolism, Interleukin-17 immunology, Interleukin-6 immunology, Interleukin-6 metabolism, Mice, Mice, Inbred C57BL, Muscle, Smooth, Vascular pathology, Myocytes, Smooth Muscle drug effects, Myocytes, Smooth Muscle metabolism, Myocytes, Smooth Muscle pathology, Plaque, Atherosclerotic immunology, Plaque, Atherosclerotic metabolism, Receptors, LDL deficiency, Receptors, LDL metabolism, Smad7 Protein deficiency, Smad7 Protein metabolism, T-Lymphocytes drug effects, Th17 Cells drug effects, Th17 Cells metabolism, Interleukin-17 metabolism, Plaque, Atherosclerotic pathology, Signal Transduction drug effects, T-Lymphocytes metabolism, Transforming Growth Factor beta metabolism
- Abstract
Adaptive immunity has a major impact on atherosclerosis, with pro- and anti-atherosclerotic effects exerted by different subpopulations of T cells. Transforming growth factor-β (TGF-β) may promote development either of anti-atherosclerotic regulatory T cells or of T helper 17 (TH17) cells, depending on factors in the local milieu. We have addressed the effect on atherosclerosis of enhanced TGF-β signaling in T cells. Bone marrow from mice with a T cell-specific deletion of Smad7, a potent inhibitor of TGF-β signaling, was transplanted into hypercholesterolemic Ldlr(-/-) mice. Smad7-deficient mice had significantly larger atherosclerotic lesions that contained large collagen-rich caps, consistent with a more stable phenotype. The inflammatory cytokine interleukin-6 (IL-6) was expressed in the atherosclerotic aorta, and increased mRNA for IL-17A and the TH17-specific transcription factor RORγt were detected in draining lymph nodes. Treating Smad7-deficient chimeras with neutralizing IL-17A antibodies reversed stable cap formation. IL-17A stimulated collagen production by human vascular smooth muscle cells, and RORγt mRNA correlated positively with collagen type I and α-smooth muscle actin mRNA in a biobank of human atherosclerotic plaques. These data link IL-17A to induction of a stable plaque phenotype, could lead to new plaque-stabilizing therapies, and should prompt an evaluation of cardiovascular events in patients treated with IL-17 receptor blockade.
- Published
- 2013
- Full Text
- View/download PDF