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.
View: Text | PDF
Research Article Autoimmunity

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

×

Figure 10

In vivo overexpression of soluble biglycan in healthy mice enhances renal and plasma levels of proinflammatory chemokines and cytokines via TLR4 and TLR2.

Options: View larger image (or click on image) Download as PowerPoint
In vivo overexpression of soluble biglycan in healthy mice enhances rena...
Ten-week-old WT (C57BL/6), Tlr2–/–, Tlr4–/–, and Tlr2–/–/Tlr4-m mice were injected intravenously with hBGN pLIVE or with an empty pLIVE vector or solvent to generate respective control mice, and 7 days following transfection were analyzed for CXCL13 (A), TNF-α (B), IL-1β (C), RANTES (D), MCP-1 (E), and MIP-1α (F) protein in total kidney homogenates using ELISA. Chemokine and cytokine levels were normalized to total protein. Renal levels of all analyzed chemokines and cytokines, enhanced by the overexpression of soluble biglycan, were partially reduced in hBGNTlr2–/–, markedly decreased in hBGNTlr4–/–, and completely abrogated in kidneys from hBGNTlr2–/–/Tlr4-m mice. Data are given as mean ± SD, and asterisks indicate statistical significance; n = 6. *P < 0.05.