Selected Publication:

SHR Neuro Cancer Cardio Lipid Metab Microb

Schaefer, L; Babelova, A; Kiss, E; Hausser, HJ; Baliova, M; Krzyzankova, M; Marsche, G; Young, MF; Mihalik, D; Götte, M; Malle, E; Schaefer, RM; Gröne, HJ.
The matrix component biglycan is proinflammatory and signals through Toll-like receptors 4 and 2 in macrophages.
J Clin Invest. 2005; 115(8): 2223-2233. Doi: 10.1172/JCI23755 [OPEN ACCESS]
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Co-authors Med Uni Graz

Malle Ernst

Marsche Gunther

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Abstract:

Biglycan, a small leucine-rich proteoglycan, is a ubiquitous ECM component; however, its biological role has not been elucidated in detail. Here we show that biglycan acts in macrophages as an endogenous ligand of TLR4 and TLR2, which mediate innate immunity, leading to rapid activation of p38, ERK, and NF-kappaB and thereby stimulating the expression of TNF-alpha and macrophage inflammatory protein-2 (MIP-2). In agreement, the stimulatory effects of biglycan are significantly reduced in TLR4-mutant (TLR4-M), TLR2-/-, and myeloid differentiation factor 88-/- (MyD88-/-) macrophages and completely abolished in TLR2-/-/TLR4-M macrophages. Biglycan-null mice have a considerable survival benefit in LPS- or zymosan-induced sepsis due to lower levels of circulating TNF-alpha and reduced infiltration of mononuclear cells in the lung, which cause less end-organ damage. Importantly, when stimulated by LPS-induced proinflammatory factors, macrophages themselves are able to synthesize biglycan. Thus, biglycan, upon release from the ECM or from macrophages, can boost inflammation by signaling through TLR4 and TLR2, thereby enhancing the synthesis of TNF-alpha and MIP-2. Our results provide evidence for what is, to our knowledge, a novel role of the matrix component biglycan as a signaling molecule and a crucial proinflammatory factor. These findings are potentially relevant for the development of new strategies in the treatment of sepsis.

Find related publications in this database (using NLM MeSH Indexing)

Adaptor Proteins, Signal Transducing -

Animals -

Antigens, Differentiation - genetics

Extracellular Matrix - genetics

Extracellular Matrix Proteins - genetics

Inflammation - genetics

Lipopolysaccharides - toxicity

Lung - metabolism

Macrophages, Alveolar - metabolism

Membrane Glycoproteins - genetics

Mice - genetics

Mice, Knockout - genetics

Myeloid Differentiation Factor 88 - genetics

NF-kappa B - metabolism

Proteoglycans - genetics

Receptors, Cell Surface - genetics

Receptors, Immunologic - genetics

Sepsis - chemically induced

Signal Transduction - drug effects

Toll-Like Receptor 2 - drug effects

Toll-Like Receptor 4 - drug effects

Toll-Like Receptors - drug effects

Tumor Necrosis Factor-alpha - biosynthesis

Zymosan - toxicity

p38 Mitogen-Activated Protein Kinases - metabolism

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