Biglycan-triggered TLR-2- and TLR-4-signaling exacerbates the pathophysiology of ischemic acute kidney injury.
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.
Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie/ZAFES, Klinikum der JW Goethe-Universität, Frankfurt am Main, Germany.
Kristin
K
Moreth
Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie/ZAFES, Klinikum der JW Goethe-Universität, Frankfurt am Main, Germany.
Helena
H
Frey
Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie/ZAFES, Klinikum der JW Goethe-Universität, Frankfurt am Main, Germany.
Mario
M
Hubo
Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie/ZAFES, Klinikum der JW Goethe-Universität, Frankfurt am Main, Germany.
Jinyang
J
Zeng-Brouwers
Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie/ZAFES, Klinikum der JW Goethe-Universität, Frankfurt am Main, Germany.
Madalina-Viviana
MV
Nastase
Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie/ZAFES, Klinikum der JW Goethe-Universität, Frankfurt am Main, Germany.
Louise Tzung-Harn
LT
Hsieh
Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie/ZAFES, Klinikum der JW Goethe-Universität, Frankfurt am Main, Germany.
Riad
R
Haceni
Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie/ZAFES, Klinikum der JW Goethe-Universität, Frankfurt am Main, Germany.
Josef
J
Pfeilschifter
Department of Pathology, Anatomy and Cell Biology, and the Cancer Cell Biology and Signaling Program, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA.
Renato V
RV
Iozzo
Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie/ZAFES, Klinikum der JW Goethe-Universität, Frankfurt am Main, Germany. Electronic address: schaefer@med.uni-frankfurt.de.
Liliana
L
Schaefer
D058186:Acute Kidney Injury / Q000276:immunology / Q000503:physiopathology*; D000818:Animals; D058578:Biglycan / Q000097:blood / Q000378:metabolism*; D015153:Blotting, Western; D018925:Chemokines / Q000097:blood; D016207:Cytokines / Q000097:blood; D017931:DNA Primers / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D057809:HEK293 Cells; D006801:Humans; D047468:Immunoprecipitation; D051379:Mice; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D015427:Reperfusion Injury / Q000276:immunology / Q000503:physiopathology*; D015398:Signal Transduction / Q000502:physiology*; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*
C546885:Bgn protein, mouse; D058578:Biglycan; D018925:Chemokines; D016207:Cytokines; D017931:DNA Primers; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4
Danger signal; Extracellular matrix; Inflammation; Innate immunity; Proteoglycan; Toll-like receptor