Activation of toll-like receptor-9 induces progression of renal disease in MRL-Fas(lpr) mice

FASEB J. 2004 Mar;18(3):534-6. doi: 10.1096/fj.03-0646fje. Epub 2004 Jan 20.


How bacterial or viral infections trigger flares of autoimmunity is poorly understood. As toll-like receptor (TLR)-9 activation by exogenous or endogenous CpG-DNA may contribute to disease activity of systemic lupus erythematosus, we examined the effects of CpG-oligodeoxynucleotides (ODN) or DNA derived from Escherichia coli (E. coli) on the course of nephritis in MRL(lpr/lpr) mice. In kidneys of these mice, TLR9 localized to glomerular, tubulointerstitial, and perivascular infiltrates. After intraperitoneal injection labeled CpG-ODN localized to glomerular and interstitial macrophages and dendritic cells in nephritic kidneys of MRL(lpr/lpr) mice but not in healthy MRL controls. Furthermore, murine J774 macrophages and splenocytes from MRL(lpr/lpr) mice, but not tubular epithelial cells, renal fibroblasts, or mesangial cells, expressed TLR9 and up-regulated CCL5/RANTES mRNA upon stimulation with CpG-ODN in vitro. In vivo both E. coli DNA and CpG-ODN increased serum DNA autoantibodies of the IgG2a isotype in MRL(lpr/lpr) mice. This was associated with progression of mild to crescentic glomerulonephritis, interstitial fibrosis, and heavy proteinuria. CpG-ODN increased renal CCL2/MCP-1 and CCL5/RANTES expression associated with increased glomerular and interstitial leukocyte recruitment. In contrast control GpC-ODN had no effect. We conclude that TLR9 activation triggers disease activity of systemic autoimmunity, for example, lupus nephritis, and that adaptive and innate immune mechanisms contribute to the CpG-DNA-induced progression of lupus nephritis.

MeSH terms

  • Animals
  • Antibodies, Antinuclear / biosynthesis*
  • Antibodies, Antinuclear / blood
  • Cells, Cultured / drug effects
  • Cells, Cultured / metabolism
  • Chemokines / biosynthesis
  • Chemokines / genetics
  • DNA / immunology*
  • DNA, Bacterial / pharmacology*
  • DNA-Binding Proteins / drug effects
  • DNA-Binding Proteins / physiology*
  • Dendritic Cells / drug effects
  • Dendritic Cells / metabolism
  • Disease Models, Animal
  • Disease Progression
  • Escherichia coli / genetics
  • Immunoglobulin G / biosynthesis*
  • Immunoglobulin G / blood
  • Kidney Glomerulus / drug effects
  • Kidney Glomerulus / immunology
  • Kidney Glomerulus / metabolism
  • Lupus Nephritis / blood
  • Lupus Nephritis / immunology
  • Lupus Nephritis / metabolism*
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Mice
  • Mice, Inbred MRL lpr
  • Oligodeoxyribonucleotides / pharmacology*
  • Receptors, CCR5 / biosynthesis
  • Receptors, CCR5 / genetics
  • Receptors, Cell Surface / drug effects
  • Receptors, Cell Surface / physiology*
  • Toll-Like Receptor 9


  • Antibodies, Antinuclear
  • CPG-oligonucleotide
  • Chemokines
  • DNA, Bacterial
  • DNA-Binding Proteins
  • Immunoglobulin G
  • Oligodeoxyribonucleotides
  • Receptors, CCR5
  • Receptors, Cell Surface
  • Tlr9 protein, mouse
  • Toll-Like Receptor 9
  • DNA