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Title: | Toll-like receptor 9 enhances nephritogenic immunity and glomerular leukocyte recruitment, exacerbating experimental crescentic glomerulonephritis. | Authors: | Ooi J.D.;Gan P.-Y.;O'Sullivan K.M.;Visvanathan K.;Akira S.;Kitching A.R. ;Holdsworth S.R. ;Summers S.A.;Steinmetz O.M. | Institution: | (Summers, Steinmetz, Ooi, Gan, O'Sullivan, Visvanathan, Kitching, Holdsworth) Centre for Inflammatory Diseases, Monash University, Department of Medicine, 246 Clayton Rd, Clayton, VIC 3168, Australia (Summers, Kitching, Holdsworth) Department of Nephrology, Monash Medical Centre, Clayton, Australia (Akira) Laboratory of Host Defense, World Premier International (WPI) Immunology Frontier Research Centre, Osaka University, Osaka, Japan | Issue Date: | 12-Oct-2012 | Copyright year: | 2010 | Publisher: | Elsevier Inc. (360 Park Avenue South, New York NY 10010, United States) | Place of publication: | United States | Publication information: | American Journal of Pathology. 177 (5) (pp 2234-2244), 2010. Date of Publication: November 2010. | Abstract: | Glomerular disease can be triggered or exacerbated by microbes that activate the immune system by Toll-like receptor (TLR) ligation. TLR9 activation promotes host defenses through the enhancement of innate and adaptive immune responses that facilitate the recruitment of leukocytes to areas of inflammation. We defined the role of TLR9 in experimental crescentic glomerulonephritis. Wild-type mice administered a TLR9 ligand and sheep anti-mouse glomerular basement membrane antibody developed histological injury with impaired renal function, which was attenuated in TLR9 knockout mice. Consistent with enhanced renal injury, wild-type mice exhibited enhanced T helper 1 and T helper 17 cellular immune responses. Kidney mRNA expression of inflammatory cytokines and chemokines as well as leukocyte recruitment were increased in wild-type mice. The use of bone marrow chimeric mice demonstrated that while both bone marrow and tissue cell TLR9 are required for maximal injury, bone marrow TLR9 is more important. Administration of a TLR9 inhibitor before sheep anti-mouse glomerular basement membrane globulin in wild-type mice attenuated cellular nephritogenic immunity that resulted in decreased renal injury. Administration of the inhibitor 7 days after disease initiation decreased glomerular leukocyte recruitment as well as renal injury. These results define the role of TLR9 in experimental crescentic glomerulonephritis and identify therapeutic potential for TLR9 inhibitors in attenuating renal injury, decreasing cellular nephritogenic immunity early in disease, and decreasing kidney effector responses later. Copyright © American Society for Investigative Pathology. | DOI: | http://monash.idm.oclc.org/login?url=http://dx.doi.org/10.2353/ajpath.2010.100153 | PubMed URL: | 20847283 [http://www.ncbi.nlm.nih.gov/pubmed/?term=20847283] | ISSN: | 0002-9440 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/30895 | Type: | Article | Subjects: | humoral immunity *immunity immunostimulation inflammation innate immunity kidney dysfunction kidney injury/dt [Drug Therapy] knockout mouse *leukocyte male mouse *nephron nonhuman chemokine/ec [Endogenous Compound] CXCL9 chemokine/ec [Endogenous Compound] cytokine/ec [Endogenous Compound] gamma interferon/ec [Endogenous Compound] immunoglobulin G/ec [Endogenous Compound] interleukin 1beta/ec [Endogenous Compound] messenger RNA/ec [Endogenous Compound] monocyte chemotactic protein 1/ec [Endogenous Compound] RANTES/ec [Endogenous Compound] receptor blocking agent/pd [Pharmacology] *toll like receptor 9/ec [Endogenous Compound] transcription factor GATA 3/ec [Endogenous Compound] transcription factor T bet/ec [Endogenous Compound] tumor necrosis factor/ec [Endogenous Compound] unclassified drug irs 869/dt [Drug Therapy] irs 869/ip [Intraperitoneal Drug Administration] irs 869/pd [Pharmacology] toll like receptor 9 inhibitor/dt [Drug Therapy] toll like receptor 9 inhibitor/pd [Pharmacology] animal model receptor upregulation sheep Th1 cell Th17 cell wild type basement membrane antibody adaptive immunity animal cell animal experiment priority journal animal tissue article bone marrow cellular immunity chimera controlled study disease exacerbation effector cell gene expression *glomerulonephritis/et [Etiology] histology effector cell gene expression *glomerulonephritis / *etiology histology humoral immunity *immunity immunostimulation inflammation innate immunity kidney dysfunction kidney injury / drug therapy knockout mouse *leukocyte male mouse *nephron nonhuman priority journal receptor upregulation animal experiment Th1 cell Th17 cell wild type animal cell adaptive immunity sheep animal model animal tissue article bone marrow cellular immunity chimera controlled study disease exacerbation |
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