Involvement of renal tubular toll-like receptor 9 in the development of tubulointerstitial injury in systemic lupus

Ariela Benigni, Cristina Caroli, Lorena Longaretti, Elena Gagliardini, Carla Zoja, Miriam Galbusera, Daniela Moioli, Paola Romagnani, Angela Tincani, Laura Andreoli, Giuseppe Remuzzi

Research output: Contribution to journalArticle

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Abstract

Objective. 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. Methods. TLR-9 was analyzed in selectively retrieved renal tissue from (NZB x NZW)F 1 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. Results. Renal tissue from NZB x 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. Conclusion. 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.

Original languageEnglish
Pages (from-to)1569-1578
Number of pages10
JournalArthritis and Rheumatism
Volume56
Issue number5
DOIs
Publication statusPublished - May 2007

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Toll-Like Receptor 9
Kidney
Wounds and Injuries
Lupus Nephritis
Antigen-Antibody Complex
Proteinuria
DNA
Laser Capture Microdissection
Cyclin-Dependent Kinases
Reverse Transcriptase Polymerase Chain Reaction
Serum
Oligonucleotides

ASJC Scopus subject areas

  • Immunology
  • Rheumatology

Cite this

Involvement of renal tubular toll-like receptor 9 in the development of tubulointerstitial injury in systemic lupus. / Benigni, Ariela; Caroli, Cristina; Longaretti, Lorena; Gagliardini, Elena; Zoja, Carla; Galbusera, Miriam; Moioli, Daniela; Romagnani, Paola; Tincani, Angela; Andreoli, Laura; Remuzzi, Giuseppe.

In: Arthritis and Rheumatism, Vol. 56, No. 5, 05.2007, p. 1569-1578.

Research output: Contribution to journalArticle

Benigni, Ariela ; Caroli, Cristina ; Longaretti, Lorena ; Gagliardini, Elena ; Zoja, Carla ; Galbusera, Miriam ; Moioli, Daniela ; Romagnani, Paola ; Tincani, Angela ; Andreoli, Laura ; Remuzzi, Giuseppe. / Involvement of renal tubular toll-like receptor 9 in the development of tubulointerstitial injury in systemic lupus. In: Arthritis and Rheumatism. 2007 ; Vol. 56, No. 5. pp. 1569-1578.
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abstract = "Objective. 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. Methods. TLR-9 was analyzed in selectively retrieved renal tissue from (NZB x NZW)F 1 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. Results. Renal tissue from NZB x 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. Conclusion. 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.",
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AU - Zoja, Carla

AU - Galbusera, Miriam

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AB - Objective. 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. Methods. TLR-9 was analyzed in selectively retrieved renal tissue from (NZB x NZW)F 1 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. Results. Renal tissue from NZB x 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. Conclusion. 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.

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