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

Shaun Andrew Summers, Betty S van der Veen, Kim O'Sullivan, Poh-Yi Gan, Joshua Ooi, Peter Heeringa, Simon C Satchell, Peter W Mathieson, Moin A Saleem, Kumar Visvanathan, Stephen Roger Holdsworth, Arthur Richard Kitching

Research output: Contribution to journalArticleResearchpeer-review

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.Kidney International advance online publication, 15 September 2010; doi:10.1038/ki.2010.327.
Original languageEnglish
Pages (from-to)1263 - 1274
Number of pages12
JournalKidney International
Volume78
Issue number12
DOIs
Publication statusPublished - 2010

Cite this

Summers, Shaun Andrew ; van der Veen, Betty S ; O'Sullivan, Kim ; Gan, Poh-Yi ; Ooi, Joshua ; Heeringa, Peter ; Satchell, Simon C ; Mathieson, Peter W ; Saleem, Moin A ; Visvanathan, Kumar ; Holdsworth, Stephen Roger ; Kitching, Arthur Richard. / Intrinsic renal cell and leukocyte-derived TLR4 aggravate experimental anti-MPO glomerulonephritis. In: Kidney International. 2010 ; Vol. 78, No. 12. pp. 1263 - 1274.
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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.Kidney International advance online publication, 15 September 2010; doi:10.1038/ki.2010.327.",
author = "Summers, {Shaun Andrew} and {van der Veen}, {Betty S} and Kim O'Sullivan and Poh-Yi Gan and Joshua Ooi and Peter Heeringa and Satchell, {Simon C} and Mathieson, {Peter W} and Saleem, {Moin A} and Kumar Visvanathan and Holdsworth, {Stephen Roger} and Kitching, {Arthur Richard}",
year = "2010",
doi = "10.1038/ki.2010.327",
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Summers, SA, van der Veen, BS, O'Sullivan, K, Gan, P-Y, Ooi, J, Heeringa, P, Satchell, SC, Mathieson, PW, Saleem, MA, Visvanathan, K, Holdsworth, SR & Kitching, AR 2010, 'Intrinsic renal cell and leukocyte-derived TLR4 aggravate experimental anti-MPO glomerulonephritis' Kidney International, vol. 78, no. 12, pp. 1263 - 1274. https://doi.org/10.1038/ki.2010.327

Intrinsic renal cell and leukocyte-derived TLR4 aggravate experimental anti-MPO glomerulonephritis. / Summers, Shaun Andrew; van der Veen, Betty S; O'Sullivan, Kim; Gan, Poh-Yi; Ooi, Joshua; Heeringa, Peter; Satchell, Simon C; Mathieson, Peter W; Saleem, Moin A; Visvanathan, Kumar; Holdsworth, Stephen Roger; Kitching, Arthur Richard.

In: Kidney International, Vol. 78, No. 12, 2010, p. 1263 - 1274.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Intrinsic renal cell and leukocyte-derived TLR4 aggravate experimental anti-MPO glomerulonephritis

AU - Summers, Shaun Andrew

AU - van der Veen, Betty S

AU - O'Sullivan, Kim

AU - Gan, Poh-Yi

AU - Ooi, Joshua

AU - Heeringa, Peter

AU - Satchell, Simon C

AU - Mathieson, Peter W

AU - Saleem, Moin A

AU - Visvanathan, Kumar

AU - Holdsworth, Stephen Roger

AU - Kitching, Arthur Richard

PY - 2010

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N2 - 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 advance online publication, 15 September 2010; doi:10.1038/ki.2010.327.

AB - 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 advance online publication, 15 September 2010; doi:10.1038/ki.2010.327.

U2 - 10.1038/ki.2010.327

DO - 10.1038/ki.2010.327

M3 - Article

VL - 78

SP - 1263

EP - 1274

JO - Kidney International

JF - Kidney International

SN - 0085-2538

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ER -