title: Transforming growth factor-β signaling in T cells promotes stabilization of atherosclerotic plaques through an interleukin-17-dependent pathway.
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.
authors.affiliation: Center for Molecular Medicine, Department of Medicine, Karolinska University Hospital, Karolinska Institutet, SE-17176 Stockholm, Sweden.
authors.forename: Anton
authors.initials: A
authors.lastname: Gisterå
authors.forename: Anna-Karin L
authors.initials: AK
authors.lastname: Robertson
authors.forename: John
authors.initials: J
authors.lastname: Andersson
authors.forename: Daniel F J
authors.initials: DF
authors.lastname: Ketelhuth
authors.forename: Olga
authors.initials: O
authors.lastname: Ovchinnikova
authors.forename: Stefan K
authors.initials: SK
authors.lastname: Nilsson
authors.forename: Anna M
authors.initials: AM
authors.lastname: Lundberg
authors.forename: Ming O
authors.initials: MO
authors.lastname: Li
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Göran K
authors.initials: GK
authors.lastname: Hansson
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001011:Aorta / Q000473:pathology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000473:pathology; D002678:Chimera; D003094:Collagen / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D019426:Integrases / Q000378:metabolism; D020381:Interleukin-17 / Q000276:immunology / Q000378:metabolism*; D015850:Interleukin-6 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D058226:Plaque, Atherosclerotic / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D011973:Receptors, LDL / Q000172:deficiency / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051906:Smad7 Protein / Q000172:deficiency / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D058504:Th17 Cells / Q000187:drug effects / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D057134:Antibodies, Neutralizing; D020381:Interleukin-17; D015850:Interleukin-6; D011973:Receptors, LDL; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D016212:Transforming Growth Factor beta; D003094:Collagen; C045073:Cre recombinase; D019426:Integrases