Recipient Toll-like receptors contribute to chronic graft dysfunction by both MyD88- and TRIF-dependent signaling.
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.
Wang
Shijun
S
Department of Cellular and Molecular Pathology, German Cancer Research Center, D-69120 Heidelberg, Germany.
Schmaderer
Christoph
C
Kiss
Eva
E
Schmidt
Claudia
C
Bonrouhi
Mahnaz
M
Porubsky
Stefan
S
Gretz
Norbert
N
Schaefer
Liliana
L
Kirschning
Carsten J
CJ
Popovic
Zoran V
ZV
Gröne
Hermann-Josef
HJ
D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D000818:Animals; D002452:Cell Count; D016207:Cytokines / Q000378:metabolism; D005355:Fibrosis; D006084:Graft Rejection; D016130:Immunophenotyping; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D016030:Kidney Transplantation; D008024:Ligands; D051379:Mice; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D009928:Organ Specificity; D055031:Primary Graft Dysfunction / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014184:Transplantation, Homologous
D033942:Adaptor Proteins, Vesicular Transport; D016207:Cytokines; D008024:Ligands; D053594:Myeloid Differentiation Factor 88; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; C476286:Ticam1 protein, mouse