Abstract |
Toll-like receptors (TLRs) recognize specific molecular patterns derived from microbial components (exogenous ligands) or stressed cells (endogenous ligands). Stimulation of these receptors leads to a pronounced inflammatory response in a variety of acute animal models. Chronic allograft dysfunction (CAD) was regarded as a candidate disease to test whether TLRs influence chronic fibrosing inflammation. Potential endogenous renal TLR ligands, specifically for TLR2 and TLR4, have now been detected by a significant upregulation of glucose regulated protein (GRP)-94, fibrinogen, heat shock protein (HSP)-60, HSP-70, biglycan (Bgn) and high-mobility group box chromosomal protein 1 (HMGB1) in the acute and chronic transplant setting. In a genetic approach to define the contribution of TLR2 and TLR4, and their adaptor proteins MyD88 and TRIF [Toll/interleukin (IL)-1 receptor domain-containing adaptor-protein inducing interferon beta], to CAD, kidney transplantation of TLR wild-type grafts to recipients who were deficient in TLR2, TLR4, TLR2/4, MyD88 and TRIF was performed. TLR and adaptor protein deficiencies significantly improved the excretory function of chronic kidney grafts by between 65% and 290%, and histopathologic signs of chronic allograft damage were significantly ameliorated. T cells, dendritic cells (DCs) and foremost macrophages were reduced in grafts by up to 4.5-fold. The intragraft concentrations of IL-6, IL-10, monocyte chemotactic protein-1 (MCP-1) and IL-12p70 were significantly lower. TLR-, MyD88- and TRIF-deficient recipients showed a significant reduction in fibrosis. alpha-smooth muscle actin (alpha-SMA)-positive cells were decreased by up to ninefold, and collagen I and III were reduced by up to twofold. These findings highlight the functional relevance of TLRs and their two major signaling pathways in graft-infiltrating mononuclear cells in the pathophysiology of CAD. A TLR signaling blockade may be a therapeutic option for the prevention of CAD.
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Authors | Shijun Wang, Christoph Schmaderer, Eva Kiss, Claudia Schmidt, Mahnaz Bonrouhi, Stefan Porubsky, Norbert Gretz, Liliana Schaefer, Carsten J Kirschning, Zoran V Popovic, Hermann-Josef Gröne |
Journal | Disease models & mechanisms
(Dis Model Mech)
Vol. 3
Issue 1-2
Pg. 92-103
( 2010)
ISSN: 1754-8411 [Electronic] England |
PMID | 20038715
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Adaptor Proteins, Vesicular Transport
- Cytokines
- Ligands
- Myeloid Differentiation Factor 88
- TICAM-1 protein, mouse
- Toll-Like Receptor 2
- Toll-Like Receptor 4
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Topics |
- Adaptor Proteins, Vesicular Transport
(metabolism)
- Animals
- Cell Count
- Cytokines
(metabolism)
- Fibrosis
- Graft Rejection
- Immunophenotyping
- Kidney
(metabolism, pathology)
- Kidney Transplantation
- Ligands
- Mice
- Myeloid Differentiation Factor 88
(metabolism)
- Organ Specificity
- Primary Graft Dysfunction
(metabolism)
- Signal Transduction
- Time Factors
- Toll-Like Receptor 2
(metabolism)
- Toll-Like Receptor 4
(metabolism)
- Transplantation, Homologous
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