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Intrinsic renal cell and leukocyte-derived TLR4 aggravate experimental anti-MPO glomerulonephritis

Summers, S. A., van der Veen, B. S., O'Sullivan, K. M., Gan, P-Y., Ooi, J. D., Heeringa, P., Satchell, S. C., Mathieson, P. W., Saleem, M. A., Visvanathan, K., Holdsworth, S. R. & Kitching, A. R., Dec-2010, In : Kidney International. 78, 12, p. 1263-1274 12 p.

Research output: Contribution to journalArticleAcademicpeer-review

  • Shaun A. Summers
  • Betty S. van der Veen
  • Kim M. O'Sullivan
  • Poh-Yi Gan
  • Joshua D. Ooi
  • Peter Heeringa
  • Simon C. Satchell
  • Peter W. Mathieson
  • Moin A. Saleem
  • Kumar Visvanathan
  • Stephen R. Holdsworth
  • A. Richard Kitching

Antimyeloperoxidase antibodies can cause crescentic glomerulonephritis and pulmonary hemorrhage. Toll-like receptors (TLRs) respond to infectious agents activating host defenses, whereas infections potentially initiate disease and provoke relapses. Neutrophils were found to be key effector cells of injury in experimental models, as disease does not occur in their absence and injury is enhanced by lipopolysaccharide (LPS). In this study, highly purified LPS (a pure TLR4 ligand) acted with antimyeloperoxidase antibodies to synergistically increase kidney and lung neutrophil recruitment and functional injury; effects abrogated in TLR4-deficient mice. Increased kidney TLR4 expression after stimulation predominantly occurred in glomerular endothelial cells. Enhanced glomerular neutrophil recruitment correlated with increased kidney mRNA expression of CXCL1 and CXCL2 (homologs of human CXCL8), whereas their preemptive neutralization decreased neutrophil recruitment. Disease induction in bone marrow chimeric mice showed that TLR4 in both bone marrow and renal parenchymal cells is required for maximal neutrophil recruitment and glomerular injury. Further studies in human glomerular cell lines stimulated with LPS found that glomerular endothelial cells were the prominent sources of CXCL8. Thus, our results define a role for TLR4 expression in bone marrow-derived and glomerular endothelial cells in neutrophil recruitment and subsequent functional and histological renal injury in experimental antimyeloperoxidase glomerulonephritis. Kidney International (2010) 78, 1263-1274; doi:10.1038/ki.2010.327; published online 15 September 2010

Original languageEnglish
Pages (from-to)1263-1274
Number of pages12
JournalKidney International
Volume78
Issue number12
Publication statusPublished - Dec-2010

    Keywords

  • anti-MPO antibody, chemokine, endothelial cell, neutrophil, TOLL-LIKE RECEPTORS, ANTINEUTROPHIL CYTOPLASMIC AUTOANTIBODIES, NEUTROPHIL CHEMOTACTIC FACTOR, INTERACTIONS IN-VIVO, CRESCENTIC GLOMERULONEPHRITIS, ANTIMYELOPEROXIDASE ANTIBODIES, MEDIATED GLOMERULONEPHRITIS, WEGENERS-GRANULOMATOSIS, CHEMOKINE RECEPTORS, EXPRESSION

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