Involvement of renal tubular toll-like receptor 9 in the development of tubulointerstitial injury in systemic lupus
Version of Record online: 27 APR 2007
Copyright © 2007 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 56, Issue 5, pages 1569–1578, May 2007
How to Cite
Benigni, A., Caroli, C., Longaretti, L., Gagliardini, E., Zoja, C., Galbusera, M., Moioli, D., Romagnani, P., Tincani, A., Andreoli, L. and Remuzzi, G. (2007), Involvement of renal tubular toll-like receptor 9 in the development of tubulointerstitial injury in systemic lupus. Arthritis & Rheumatism, 56: 1569–1578. doi: 10.1002/art.22524
- Issue online: 27 APR 2007
- Version of Record online: 27 APR 2007
- Manuscript Accepted: 16 JAN 2007
- Manuscript Received: 24 OCT 2006
- Fellowship from Fondazione ARMR (Aiuti per la Ricerca sulle Malattie Rare), Bergamo, Italy
- Fellowship from Fondazione Cariplo, Milan, Italy
Toll-like receptor 9 (TLR-9), a receptor for CpG DNA, has been implicated in the activation of immune cells in lupus. We undertook this study to determine whether the expression of TLR-9 in resident renal cells in lupus nephritis is related to the development of tubulointerstitial injury.
TLR-9 was analyzed in selectively retrieved renal tissue from (NZB × NZW)F1 mice at different stages of disease by laser capture microdissection combined with real-time quantitative reverse transcriptase–polymerase chain reaction, and in renal biopsy specimens from lupus nephritis patients by immunohistochemistry. We investigated for the molecular component responsible for TLR-9 activation by cultured proximal tubular cells in serum from patients with lupus.
Renal tissue from NZB × NZW mice displayed robust TLR-9 expression localized to proximal tubular cells. TLR-9 levels correlated with proteinuria and tubulointerstitial injury to the extent that a cyclin-dependent kinase inhibitor, while reducing proteinuria and renal structural damage, prevented tubular TLR-9 generation in lupus mice. Consistently, exaggerated TLR-9 staining was found in proximal tubular cells of lupus patients, which correlated with tubulointerstitial damage. DNA-containing immune complexes purified from sera of patients with lupus induced TLR-9 in cultured proximal tubular cells. This was prevented by CCGG-rich short oligonucleotides, specific antagonists of CpG DNA, indicating that the DNA component of immune complexes was required for TLR-9 stimulation.
These findings suggest that tubular TLR-9 activation has a pathogenetic role in tubulointerstitial inflammation and damage in experimental and human lupus nephritis, and they indicate a novel target for future therapies.