Smooth Muscle Cell-Derived Interleukin-17C Plays an Atherogenic Role via the Recruitment of Proinflammatory Interleukin-17A+ T Cells to the Aorta

Arterioscler Thromb Vasc Biol. 2016 Aug;36(8):1496-506. doi: 10.1161/ATVBAHA.116.307892. Epub 2016 Jun 30.

Abstract

Objective: 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.

Approach and results: 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.

Conclusions: Smooth muscle cell-derived IL-17C plays a proatherogenic role by supporting the recruitment of Th17 cells to atherosclerotic lesions.

Keywords: atherosclerosis; cytokines; inflammation; leukocytes; smooth muscle cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aorta / metabolism
  • Aorta / pathology
  • Aortic Diseases / genetics
  • Aortic Diseases / metabolism*
  • Aortic Diseases / pathology
  • Aortic Diseases / prevention & control
  • Apolipoproteins E / deficiency
  • Apolipoproteins E / genetics
  • Atherosclerosis / genetics
  • Atherosclerosis / metabolism*
  • Atherosclerosis / pathology
  • Atherosclerosis / prevention & control
  • Cells, Cultured
  • Chemotaxis, Leukocyte*
  • Collagen Type I / metabolism
  • Diet, High-Fat
  • Disease Models, Animal
  • Female
  • Fibroblasts / metabolism
  • Genetic Predisposition to Disease
  • Inflammation / genetics
  • Inflammation / metabolism*
  • Inflammation / pathology
  • Inflammation / prevention & control
  • Interleukin-17 / deficiency
  • Interleukin-17 / genetics
  • Interleukin-17 / metabolism*
  • Male
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Muscle, Smooth, Vascular / metabolism*
  • Muscle, Smooth, Vascular / pathology
  • Myocytes, Smooth Muscle / metabolism*
  • Myocytes, Smooth Muscle / pathology
  • Paracrine Communication*
  • Phenotype
  • Plaque, Atherosclerotic
  • Signal Transduction
  • T-Lymphocytes, Regulatory / metabolism
  • Th17 Cells / metabolism*
  • Th17 Cells / pathology

Substances

  • Apolipoproteins E
  • Collagen Type I
  • Il17a protein, mouse
  • Il17c protein, mouse
  • Interleukin-17
  • collagen type I, alpha 1 chain