Pathogenic anti-DNA antibodies modulate gene expression in mesangial cells: involvement of HMGB1 in anti-DNA antibody-induced renal injury

Immunol Lett. 2008 Nov 16;121(1):61-73. doi: 10.1016/j.imlet.2008.08.007. Epub 2008 Sep 24.

Abstract

Although anti-DNA antibodies have been decisively linked to the pathogenesis of lupus nephritis, the mechanisms have not been conclusively determined. Recently, we reported that anti-DNA antibodies may contribute to kidney damage by upregulation of proinflammatory genes in mesangial cells (MC), a process involving both Fc receptor-dependent and independent pathways. In investigating the mechanism by which pathogenic anti-DNA antibodies modulate gene expression in MC, we found that the pathogenic anti-DNA antibody 1A3F bound to high mobility group binding protein 1 (HMGB1), an endogenous ligand for TLR2/4 and RAGE (receptor for advanced glycation end products). Interestingly, HMGB1 treatment of MC induced a similar pattern of genes as stimulation with 1A3F. Furthermore, HMGB1 and 1A3F exhibited a synergistic proinflammatory effect in the kidney, where increased expression of HMGB1 was found in lupus patients but not in patients with other types of renal disease. TLR2/Fc and RAGE/Fc inhibited the proinflammatory effects of 1A3F on MC. Finally, we found enhanced susceptibility of lupus prone MRL-lpr/lpr (MRL/lpr) as compared to normal BALB/c derived MC to pathogenic anti-DNA antibody and LPS stimulation (in particular enhanced chemokine synthesis), in addition to significantly increased expression of TLR4. Our results suggest that gene upregulation in MC induced by nephritogenic anti-DNA antibodies is TLR2/4 and RAGE-dependent. Finally, HMGB1 may act as a proinflammatory mediator in antibody-induced kidney damage in systemic lupus erythematosus (SLE).

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antibodies, Antinuclear / immunology*
  • Down-Regulation / immunology
  • Female
  • Gene Expression
  • HMGB1 Protein / immunology*
  • HMGB1 Protein / metabolism
  • Humans
  • Lupus Erythematosus, Systemic / genetics
  • Lupus Erythematosus, Systemic / immunology*
  • Lupus Erythematosus, Systemic / pathology
  • Lupus Nephritis / genetics
  • Lupus Nephritis / immunology*
  • Lupus Nephritis / pathology
  • Mesangial Cells / immunology*
  • Mesangial Cells / metabolism
  • Mesangial Cells / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred MRL lpr
  • Mitogen-Activated Protein Kinases / immunology
  • Mitogen-Activated Protein Kinases / metabolism
  • Myeloid Differentiation Factor 88 / immunology
  • Myeloid Differentiation Factor 88 / metabolism
  • Toll-Like Receptor 2 / immunology
  • Toll-Like Receptor 2 / metabolism
  • Toll-Like Receptor 4 / immunology
  • Toll-Like Receptor 4 / metabolism
  • Up-Regulation / immunology

Substances

  • Antibodies, Antinuclear
  • HMGB1 Protein
  • Myd88 protein, mouse
  • Myeloid Differentiation Factor 88
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4
  • Mok protein, mouse
  • Mitogen-Activated Protein Kinases