The proteoglycan biglycan regulates expression of the B cell chemoattractant CXCL13 and aggravates murine lupus nephritis
Kristin Moreth, … , Roland M. Schaefer, Liliana Schaefer
Kristin Moreth, … , Roland M. Schaefer, Liliana Schaefer
Published November 15, 2010
Citation Information: J Clin Invest. 2010;120(12):4251-4272. https://doi.org/10.1172/JCI42213.
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The proteoglycan biglycan regulates expression of the B cell chemoattractant CXCL13 and aggravates murine lupus nephritis

Abstract

CXCL13 is a key B cell chemoattractant and marker of disease activity in patients with SLE; however, the mechanism of its induction has not been identified yet. Here, we have shown that the proteoglycan biglycan triggers CXCL13 expression via TLR2/4 in macrophages and dendritic cells. In vivo, levels of biglycan were markedly elevated in the plasma and kidneys of human SLE patients and lupus-prone (MRL/lpr) mice. Overexpression of soluble biglycan in MRL/lpr mice raised plasma and renal levels of CXCL13 and caused accumulation of B cells with an enhanced B1/B cell ratio in the kidney, worsening of organ damage, and albuminuria. Importantly, biglycan also triggered CXCL13 expression and B cell infiltration in the healthy kidney. Conversely, biglycan deficiency improved systemic and renal outcome in lupus-prone mice, with lower levels of autoantibodies, less enlargement of the spleen and lymph nodes, and reduction in renal damage and albuminuria. This correlated with a marked decline in circulating and renal CXCL13 and a reduction in the number of B cells in the kidney. Collectively, our results describe what we believe to be a novel mechanism for the regulation of CXCL13 by biglycan, a host-derived ligand for TLR2/4. Blocking biglycan-TLR2/4 interactions might be a promising strategy for the management of SLE and other B cell–mediated inflammatory disease entities.

Authors

Kristin Moreth, Rebekka Brodbeck, Andrea Babelova, Norbert Gretz, Tilmann Spieker, Jinyang Zeng-Brouwers, Josef Pfeilschifter, Marian F. Young, Roland M. Schaefer, Liliana Schaefer

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Figure 9

Biglycan triggers CXCL13 expression in spleen dendritic cells and residential macrophages in a TLR2/TLR4- and ROS-dependent manner.

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Biglycan triggers CXCL13 expression in spleen dendritic cells and reside...
Cxcl13 mRNA (A and C) and protein levels in cell culture supernatants (B, D–F) from spleen dendritic cells (A and B) and macrophages (C–F) from C57BL/6, Tlr2–/–, Tlr4–/–, Tlr2–/–/Tlr4-m, P2x7r–/–, Asc–/–, and caspase-1–/– mice were quantitatively assessed by ELISA (B, D–F) and TaqMan RT-PCR (A and C). Monocytes/macrophages and dendritic cells were isolated as described in Methods. TaqMan results (A and C) are given as average-fold induction over controls, normalized to Gapdh. Asterisks positioned over the respective bars indicate statistical significance for biglycan-stimulated cells compared with nonstimulated controls (A–D). (E and F) ELISA for CXCL13 in culture media from (E) C57BL/6 macrophages preincubated with NAC (10 mM) or DPI (0.5 mM) for 1 hour from (F) C57BL/6, P2x7r–/–, Asc–/–, and caspase-1–/– macrophages stimulated with biglycan (4 μg/ml) for 4 hours. Data are given as mean ± SD; n = 6. *P < 0.05.