title: Intrinsic renal cell and leukocyte-derived TLR4 aggravate experimental anti-MPO glomerulonephritis.
abstract: 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.
authors.affiliation: Department of Medicine, Centre for Inflammatory Diseases, Monash University, Clayton, Victoria, Australia.
authors.forename: Shaun A
authors.initials: SA
authors.lastname: Summers
authors.forename: Betty S
authors.initials: BS
authors.lastname: van der Veen
authors.forename: Kim M
authors.initials: KM
authors.lastname: O'Sullivan
authors.forename: Poh-Yi
authors.initials: PY
authors.lastname: Gan
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Ooi
authors.forename: Peter
authors.initials: P
authors.lastname: Heeringa
authors.forename: Simon C
authors.initials: SC
authors.lastname: Satchell
authors.forename: Peter W
authors.initials: PW
authors.lastname: Mathieson
authors.forename: Moin A
authors.initials: MA
authors.lastname: Saleem
authors.forename: Kumar
authors.initials: K
authors.lastname: Visvanathan
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Holdsworth
authors.forename: A Richard
authors.initials: AR
authors.lastname: Kitching
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000009:adverse effects* / Q000276:immunology / Q000494:pharmacology; D019268:Antibodies, Antineutrophil Cytoplasmic / Q000009:adverse effects / Q000494:pharmacology; D002460:Cell Line; D054360:Chemokine CXCL1 / Q000378:metabolism; D054426:Chemokine CXCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D005921:Glomerulonephritis / Q000139:chemically induced* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D007678:Kidney Glomerulus / Q000378:metabolism / Q000473:pathology; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008070:Lipopolysaccharides / Q000009:adverse effects / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009195:Peroxidase / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*
chemical_list: D000888:Antibodies, Anti-Idiotypic; D019268:Antibodies, Antineutrophil Cytoplasmic; C508606:CXCL8 protein, human; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; D016209:Interleukin-8; D008070:Lipopolysaccharides; C495345:TLR4 protein, human; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D009195:Peroxidase