Renal IL-17 expression in human ANCA-associated glomerulonephritis

Am J Physiol Renal Physiol. 2012 Jun 15;302(12):F1663-73. doi: 10.1152/ajprenal.00683.2011. Epub 2012 Mar 21.

Abstract

Interleukin-17A (IL-17) promotes inflammatory renal tissue damage in mouse models of crescentic glomerulonephritis, including murine experimental autoimmune anti-myeloperoxidase glomerulonephritis, which most likely depends on IL-17-producing Th17 cells. In human anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis, however, the cellular sources of IL-17 remain to be elucidated. Therefore, we analyzed human kidney biopsies of active necrotizing and crescentic ANCA-associated glomerulonephritis by immunohistochemistry using an IL-17-specific antibody and by immunofluorescent colocalization with cell type markers. We detected numerous IL-17-expressing (IL-17(+)) cells in the glomeruli and in the tubulointerstitium. Unexpectedly, most of these IL-17(+) cells were polymorphonuclear neutrophilic granulocytes, while IL-17(+) T cells and IL-17(+) mast cells were present at significantly lower frequencies. IL-17 was not detected in other infiltrating or resident kidney cells. In those patients who had not received immunosuppressive treatment before biopsy, serum creatinine levels were positively correlated with tubulointerstitial IL-17(+) neutrophils as well as IL-17(+) T cells. Furthermore, we could demonstrate that purified human blood neutrophils expressed IL-17 protein and released it upon stimulation in vitro. In conclusion, these results support a pathogenic role for IL-17 in human ANCA-associated glomerulonephritis. Our data suggest that in the acute stage of the disease neutrophils may act as an important immediate-early innate source of IL-17 and may thereby initiate and promote ongoing renal inflammation. IL-17 may thus be a target for treating acute ANCA-associated glomerulonephritis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Antineutrophil Cytoplasmic / immunology
  • Antibodies, Antineutrophil Cytoplasmic / metabolism*
  • Female
  • Glomerulonephritis / immunology
  • Glomerulonephritis / metabolism*
  • Humans
  • Interleukin-17 / metabolism*
  • Kidney / immunology
  • Kidney / metabolism*
  • Male
  • Mast Cells / immunology
  • Mast Cells / metabolism
  • Middle Aged
  • Neutrophils / immunology
  • Neutrophils / metabolism

Substances

  • Antibodies, Antineutrophil Cytoplasmic
  • Interleukin-17