Recipient Toll-like receptors contribute to chronic graft dysfunction by both MyD88- and TRIF-dependent signaling

• Published in: Disease models & mechanisms 2010-01, Vol.3 (1-2), p.92-103
• Main Authors: Wang, Shijun, Schmaderer, Christoph, Kiss, Eva, Schmidt, Claudia, Bonrouhi, Mahnaz, Porubsky, Stefan, Gretz, Norbert, Schaefer, Liliana, Kirschning, Carsten J, Popovic, Zoran V, Gröne, Hermann-Josef
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Vesicular Transport - metabolism; Animals; Antigens; Cell Count; Chemokines; Creatinine; Cytokines; Cytokines - secretion; Fibrosis; Graft Rejection; Heat shock proteins; Immune system; Immunophenotyping; Kidney - metabolism; Kidney - pathology; Kidney Transplantation; Kidney transplants; Ligands; Lymphocytes; 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; Tumor necrosis factor-TNF
• ISSN: 1754-8403; 1754-8411
• DOI: 10.1242/dmm.003533

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.