The IL-23/Th17 axis contributes to renal injury in experimental glomerulonephritis

J Am Soc Nephrol. 2009 May;20(5):969-79. doi: 10.1681/ASN.2008050556. Epub 2009 Apr 1.

Abstract

T cells infiltrate the kidney in both human and experimental glomerulonephritis, and several lines of evidence indicate that T cell-mediated tissue damage plays an important role in the immunopathogenesis of renal inflammatory diseases. However, the functions of the different T cell subsets, particularly the recently identified interleukin-17 (IL-17)-producing T cells (Th17 cells), are incompletely understood in glomerulonephritis. Here, we identified renal IL-17-producing T cells in the T cell-mediated model of nephrotoxic nephritis in mice. In vitro, IL-17 enhanced the production of the proinflammatory chemokines CCL2/MCP-1, CCL3/MIP-1alpha, and CCL20/LARC, which are implicated in the recruitment of T cells and monocytes, in mouse mesangial cells. To determine the function of Th17 cells in renal inflammation, we induced nephrotoxic nephritis in IL-23 p19(-/-) mice, which have reduced numbers of Th17 cells, and in IL-17(-/-) mice, which are deficient in the effector cytokine IL-17 itself. In comparison with nephritic wild-type mice, IL-23 p19(-/-) mice demonstrated less infiltration of Th17 cells, and both IL-23 p19(-/-) and IL-17(-/-) mice developed less severe nephritis as measured by renal function, albuminuria, and frequency of glomerular crescent formation. These results demonstrate that the IL-23/IL-17 pathway significantly contributes to renal tissue injury in experimental glomerulonephritis. Targeting the IL-23/Th17 axis may be a promising therapeutic strategy for the treatment of proliferative and crescentic glomerulonephritis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chemokine CCL2 / genetics
  • Chemokine CCL2 / immunology
  • Chemokine CCL3 / genetics
  • Chemokine CCL3 / immunology
  • Chemokines / genetics
  • Disease Models, Animal
  • Glomerular Mesangium / immunology
  • Glomerular Mesangium / pathology
  • Glomerulonephritis / immunology*
  • Inflammation / immunology
  • Inflammation / pathology
  • Interleukin-17 / genetics
  • Interleukin-17 / immunology*
  • Interleukin-23 / deficiency
  • Interleukin-23 / genetics
  • Interleukin-23 / immunology*
  • Kidney / immunology*
  • Kidney / pathology
  • Mice
  • Mice, Knockout
  • Monocytes / immunology
  • RNA, Messenger / genetics
  • T-Lymphocyte Subsets / immunology*
  • Tumor Necrosis Factor-alpha / pharmacology

Substances

  • Ccl2 protein, mouse
  • Ccl3 protein, mouse
  • Chemokine CCL2
  • Chemokine CCL3
  • Chemokines
  • Interleukin-17
  • Interleukin-23
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha