title: Smooth Muscle Cell-Derived Interleukin-17C Plays an Atherogenic Role via the Recruitment of Proinflammatory Interleukin-17A+ T Cells to the Aorta.
abstract: Atherosclerosis is characterized by frequent communication between infiltrating leukocytes and vascular cells, through chemokine and cytokine networks. Interleukin-17C (IL-17C) is detectable within atherosclerotic lesions; however, the potential involvement of this cytokine has not been examined. Thus, we sought to investigate the role of IL-17C in atherosclerosis.
  
  
  
  The expression of IL-17 cytokines was profiled within aortas of apolipoprotein E double knockout (Apoe(-/-)) mice, and Il17c expression was elevated. Flow cytometry experiments revealed a major population of aortic IL-17C-producing smooth muscle cells. Next, we generated Il17c(-/-)Apoe(-/-) mice and demonstrated that atherosclerotic lesion and collagen content was diminished within Western diet-fed Il17c(-/-)Apoe(-/-) aortas and aortic roots in comparison to Apoe(-/-) controls. Smooth muscle cells and fibroblasts were mainly responsible for the reduced Col1A1 expression in the aorta of Il17c(-/-)Apoe(-/-) mice. Importantly, IL-17C-treated Apoe(-/-) aortas showed upregulated Col1A1 expression ex vivo. Il17c(-/-)Apoe(-/-) mice displayed a proportional reduction in aortic macrophages, neutrophils, T cells, T helper 1 cells, and T regulatory cells, without corresponding changes in the peripheral immune composition. Examination of aortic IL-17A(+) T-cell receptor γδ T cells and Th17 cells demonstrated a stark reduction in the percentage and number of these subsets within Il17c(-/-)Apoe(-/-) versus Apoe(-/-) mice. Explanted 12-week Western diet-fed Apoe(-/-) aortas treated with IL-17C resulted in the induction of multiple vascular chemokines and cytokines. Th17 cells demonstrated attenuated migration toward supernatants from cultures of Il17c(-/-)Apoe(-/-) smooth muscle cells, and short-term homing experiments revealed diminished recruitment of Th17 cells to the aorta of Il17c(-/-)Apoe(-/-) recipients.
  
  
  
  Smooth muscle cell-derived IL-17C plays a proatherogenic role by supporting the recruitment of Th17 cells to atherosclerotic lesions.
authors.affiliation: From the Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Butcher
authors.affiliation: From the Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk.
authors.forename: Tayab C
authors.initials: TC
authors.lastname: Waseem
authors.affiliation: From the Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk. galkinev@evms.edu.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Galkina
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte; D024042:Collagen Type I / Q000378:metabolism; D000090602:Collagen Type I, alpha 1 Chain; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D020381:Interleukin-17 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009131:Muscle, Smooth, Vascular / Q000378:metabolism* / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism* / Q000473:pathology; D019899:Paracrine Communication; D010641:Phenotype; D058226:Plaque, Atherosclerotic; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism; D058504:Th17 Cells / Q000378:metabolism* / Q000473:pathology
chemical_list: D001057:Apolipoproteins E; D024042:Collagen Type I; D000090602:Collagen Type I, alpha 1 Chain; C098680:Il17a protein, mouse; C515930:Il17c protein, mouse; D020381:Interleukin-17
keywords: atherosclerosis; cytokines; inflammation; leukocytes; smooth muscle cells