IL-17A Produced by Both γδ T and Th17 Cells Promotes Renal Fibrosis via RANTES-mediated Leukocyte Infiltration After Renal Obstruction

J Pathol. 2015 Jan;235(1):79-89. doi: 10.1002/path.4430. Epub 2014 Oct 6.

Abstract

IL-17A-producing T lymphocytes play a crucial role in inflammatory kidney diseases, but their role in renal fibrosis remains to be explored. Here, we demonstrated that up-regulation of IL-17A was associated with the development of obstructive kidney injury. The primary source of IL-17A production in obstructed kidneys was infiltrating γδ T lymphocytes and CD4(+) T cells. IL-17A-deficient mice were protected from myofibroblast activation and extracellular matrix deposition, leading to reduced kidney fibrosis in response to obstructive injury. Mechanistically, IL-17A deficiency suppressed the expression of the chemokine RANTES in infiltrated CD3(+) T cells and peritubular inflammation following renal obstruction. Administration of RANTES-neutralizing antibody significantly reduced the accumulation of T cells and macrophages, and of collagen deposition in obstructed kidneys. Taken together, our results indicate that IL-17A contributes significantly to the pathogenesis of renal fibrosis by regulating RANTES-mediated inflammatory cell infiltration.

Keywords: IL-17A; RANTES; inflammation; obstructive nephropathy; renal fibrosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chemokine CCL5 / metabolism*
  • Chemokines / metabolism
  • Fibrosis
  • Inflammation / metabolism
  • Interleukin-17 / biosynthesis*
  • Interleukin-17 / genetics
  • Kidney / pathology*
  • Kidney Diseases / immunology*
  • Kidney Diseases / pathology
  • Leukocytes / immunology*
  • Macrophages / metabolism
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Receptors, Antigen, T-Cell, gamma-delta / immunology*
  • Th17 Cells / immunology*

Substances

  • Ccl5 protein, mouse
  • Chemokine CCL5
  • Chemokines
  • Il17a protein, mouse
  • Interleukin-17
  • Receptors, Antigen, T-Cell, gamma-delta