Inhibition of IL-17A attenuates atherosclerotic lesion development in apoE-deficient mice.
The importance of an (auto)immune response in atherogenesis is becoming increasingly well understood. IL-17A-expressing T cells modulate immune cell trafficking, initiating inflammation and cytokine production in (auto)immune diseases. In human carotid artery plaques, we previously showed the presence of IL-17A-producing T cells and IL-23; however, IL-17A effects on atherogenesis have not been studied. Aortic root sections from 8-wk-old apolipoprotein E-deficient mice fed a standard chow diet were examined after 12 wk for lesion area, plaque composition, cellular infiltration, cytokine expression, and apoptosis. The treatment group (n = 15) received anti-IL-17A Ab and the controls (n = 10) received irrelevant Abs. Inhibition of IL-17A markedly reduced atherosclerotic lesion area (p < 0.001), maximal stenosis (p < 0.001), and vulnerability of the lesion. IL-17A mAb-treated mice showed reduced cellular infiltration, down-regulation of activation markers on endothelium and immune cells (e.g., VCAM-1), and reduced cytokine/chemokine secretion (e.g., IL6, TNFalpha, CCL5). To investigate possible mechanisms, different atherogenic cell types (e.g., macrophages, dendritic cells, HUVECs, vascular smooth muscle cells) were stimulated with IL-17A in addition to TNF-alpha, IFN-gamma, or LPS to induce cellular activation or apoptosis in vitro. Stimulation with IL-17A induced proinflammatory changes in several atherogenic cell types and apoptotic cell death in murine cells. Functional blockade of IL-17A reduces atherosclerotic lesion development and decreases plaque vulnerability, cellular infiltration, and tissue activation in apolipoprotein E-deficient mice. The present data support a pathogenic role of IL-17A in the development of atherosclerosis by way of its widespread proinflammatory and proapoptotic effects on atherogenic cells.
Erbel
Christian
C
Department of Cardiology, University of Heidelberg, Heidelberg, Germany. Christian.Erbel@med.uni-heidelberg.de
Chen
Lili
L
Bea
Florian
F
Wangler
Susanne
S
Celik
Sultan
S
Lasitschka
Felix
F
Wang
Ying
Y
Böckler
Dittmar
D
Katus
Hugo A
HA
Dengler
Thomas J
TJ
D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology; D050197:Atherosclerosis / Q000276:immunology* / Q000473:pathology* / Q000517:prevention & control; D002478:Cells, Cultured; D004195:Disease Models, Animal; D005260:Female; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D001057:Apolipoproteins E; D051017:Apoptosis Regulatory Proteins; C508717:IL17A protein, human; D018836:Inflammation Mediators; D020381:Interleukin-17