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The matrix component biglycan is proinflammatory and signals through Toll-like receptors 4 and 2 in macrophages
Liliana Schaefer, … , Roland M. Schaefer, Hermann-Josef Gröne
Liliana Schaefer, … , Roland M. Schaefer, Hermann-Josef Gröne
Published August 1, 2005
Citation Information: J Clin Invest. 2005;115(8):2223-2233. https://doi.org/10.1172/JCI23755.
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Research Article Immunology

The matrix component biglycan is proinflammatory and signals through Toll-like receptors 4 and 2 in macrophages

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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-κB and thereby stimulating the expression of TNF-α 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-α 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-α 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.

Authors

Liliana Schaefer, Andrea Babelova, Eva Kiss, Heinz-J. Hausser, Martina Baliova, Miroslava Krzyzankova, Gunther Marsche, Marian F. Young, Daniel Mihalik, Martin Götte, Ernst Malle, Roland M. Schaefer, Hermann-Josef Gröne

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Figure 2

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Increased expression of BGN in infiltrating cells of lung parenchyma in ...
Increased expression of BGN in infiltrating cells of lung parenchyma in sepsis. (A and B) Northern blot of BGN mRNA normalized to α-tubulin (2 hours) (A) and Western blot of BGN core protein normalized to α-tubulin (8 hours) (B) from lungs of Bgn+/0 mice after a lethal dose of LPS versus PBS. (C and D) Immunostaining of BGN (red stain) in lungs from control (C) and septic Bgn+/0 mice (D) 8 hours after a lethal dose of LPS. (E and F) Double staining, marked by arrows, for BGN (blue) and macrophages (F4/80, red) (E) and in situ hybridization for BGN (F) in septic lungs from Bgn+/0 mice (8 hours). The lower right inset shows a magnified view of mononuclear cells expressing BGN (white arrowhead). The upper left inset represents the sense riboprobe. (G and H) Immunostaining of macrophages (F4/80, red), with numerous F4/80–positive macrophages (lower right insets), in septic lungs from Bgn+/0 (G) versus Bgn–/0 mice (H). (I–L) Immunostaining of type I collagen in lungs from Bgn+/0 (brown) (I) versus Bgn–/0 mice (J) and Western blots of fibronectin (K) and laminin (L) normalized to β-tubulin in lungs from Bgn+/0 versus Bgn–/0 mice 8 hours after a lethal dose of LPS. The lower right insets in C, D, F, G, and H represent higher magnifications. Scale bars in D, H, and J apply to panels in C, G, and I, respectively.

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