Biglycan-triggered TLR-2- and TLR-4-signaling exacerbates the pathophysiology of ischemic acute kidney injury.

Abstract

Exacerbated inflammation in renal ischemia-reperfusion injury, the major cause of intrinsic acute renal failure, is a key trigger of kidney damage. During disease endogenous danger signals stimulate innate immune cells via Toll-like receptors (TLR)-2 and -4 and accelerate inflammatory responses. Here we show that production of soluble biglycan, a small leucine-rich proteoglycan, is induced during reperfusion and that it functions as endogenous agonist of TLR-2/4. Biglycan-mediated activation of TLR-2/4 initiates an inflammatory response in native kidneys, which is marked by the release of cytokines and chemokines and recruitment of inflammatory cells. Overexpression of soluble circulating biglycan before ischemic reperfusion enhanced plasma and renal levels of TNF-α, CXCL1, CCL2 and CCL5, caused influx of neutrophils, macrophages and T cells and overall worsened renal function in wild type mice. We provide robust genetic evidence for TLR-2/4 requirement insofar as biglycan biological effects were markedly dampened in mice deficient in both innate immune receptors, Tlr2(-/-);Tlr4(-/-) mice. Thus, signaling of soluble biglycan via TLR-2/4 could represent a novel therapeutic target for the prevention and possible treatment of patients with acute renal ischemia-reperfusion injury.

• Authors: Kristin Moreth, Helena Frey, Mario Hubo, Jinyang Zeng-Brouwers, Madalina-Viviana Nastase, Louise Tzung-Harn Hsieh, Riad Haceni, Josef Pfeilschifter, Renato V Iozzo, Liliana Schaefer
• Journal: Matrix biology : journal of the International Society for Matrix Biology (Matrix Biol) Vol. 35 Pg. 143-51 (Apr 2014) ISSN: 1569-1802 [Electronic] Netherlands
• PMID: 24480070 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 International Society of Matrix Biology. Published by Elsevier B.V. All rights reserved.

Chemical References

• Bgn protein, mouse
• Biglycan
• Chemokines
• Cytokines
• DNA Primers
• Tlr2 protein, mouse
• Tlr4 protein, mouse
• Toll-Like Receptor 2
• Toll-Like Receptor 4

Topics

• Acute Kidney Injury (immunology, physiopathology)
• Animals
• Biglycan (blood, metabolism)
• Blotting, Western
• Chemokines (blood)
• Cytokines (blood)
• DNA Primers (genetics)
• Enzyme-Linked Immunosorbent Assay
• HEK293 Cells
• Humans
• Immunoprecipitation
• Mice
• Mice, Knockout
• Real-Time Polymerase Chain Reaction
• Reperfusion Injury (immunology, physiopathology)
• Signal Transduction (physiology)
• Toll-Like Receptor 2 (genetics, metabolism)
• Toll-Like Receptor 4 (genetics, metabolism)