Blockade of interleukin-17A results in reduced atherosclerosis in apolipoprotein E-deficient mice.
BACKGROUND
T cells play an important role during the immune response that accompanies atherosclerosis. To date, the role for interleukin (IL)-17A in atherogenesis is not well defined. Here, we tested the hypothesis that atherosclerosis-prone conditions induce the differentiation of IL-17A-producing T cells, which in turn promote atherosclerosis.


RESULTS
IL-17A was found to be elevated in the plasma and tissues of apolipoprotein E-deficient (Apoe(-/-)) mice. IL-17A-expressing T cells were significantly increased in the aortas, spleen, and lamina propria of aged Apoe(-/-) mice compared with age-matched C57BL/6 mice. IL-17A(+) T cells resided in both adventitia and aortas of aged Apoe(-/-) mice fed a chow diet. Elevated levels of IL-17A(+) T cells were also detected in the aortas of 21-week-old Apoe(-/-) mice fed a Western diet for 15 weeks. IL-17A(+) T cells were characterized as predominantly CD4(+) T helper 17 (Th17) cells and gammadelta(+) T cells. Blockade of IL-17A in Apoe(-/-) mice by use of adenovirus-produced IL-17 receptor A reduced plaque burden in Apoe(-/-) mice fed a Western diet for 15 weeks. In addition, the treatment diminished circulating IL-6 and granulocyte colony-stimulating factor levels and limited CXCL1 expression and macrophage content within the aortas. Conversely, IL-17A treatment of whole aorta isolated from Apoe(-/-) mice promoted aortic CXCL1 expression and monocyte adhesion in an ex vivo adhesion assay.


CONCLUSIONS
These results demonstrate that atherosclerosis-prone conditions induce the differentiation of IL-17A-producing T cells. IL-17A plays a proatherogenic inflammatory role during atherogenesis by promoting monocyte/macrophage recruitment into the aortic wall.
Smith
Emily
E
Robert M. Berne Cardiovascular Research Center, University of Virginia, Charlottesville, USA.
Prasad
Konkal-Matt R
KM
Butcher
Matthew
M
Dobrian
Anca
A
Kolls
Jay K
JK
Ley
Klaus
K
Galkina
Elena
E
D000818:Animals; D001011:Aorta / Q000166:cytology / Q000276:immunology; D001057:Apolipoproteins E / Q000235:genetics*; D050197:Atherosclerosis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology; D054360:Chemokine CXCL1 / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000097:blood; D020381:Interleukin-17 / Q000037:antagonists & inhibitors / Q000097:blood*; D015850:Interleukin-6 / Q000097:blood; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009000:Monocytes / Q000166:cytology / Q000276:immunology; D009092:Mucous Membrane / Q000166:cytology / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D001057:Apolipoproteins E; D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D020381:Interleukin-17; D015850:Interleukin-6; D011993:Recombinant Fusion Proteins; D016179:Granulocyte Colony-Stimulating Factor