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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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Research Article Autoimmunity Article has an altmetric score of 8

The proteoglycan biglycan regulates expression of the B cell chemoattractant CXCL13 and aggravates murine lupus nephritis

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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 7

Influence of biglycan on the expression of pro-Il1B and Nlrp3 and levels of active caspase-1 and mature IL-1β in kidneys from MRL/lpr and MRL mice.

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Influence of biglycan on the expression of pro-Il1B and Nlrp3 and levels...
Ten-week-old Bgn+/+MRL, Bgn+/+MRL/lpr, Bgn–/–MRL/lpr, hBGN mice and their respective controls, as well as 16- and 24-week-old Bgn–/–MRL/lpr and Bgn+/+MRL/lpr mice were analyzed for pro-Il1B and Nlrp3 mRNA expression, active caspase-1, and content of mature IL-1β in total kidney homogenates. (A and B) TaqMan analysis for the renal expression of pro-Il1B (A) and Nlrp3 (B) shown as the average-fold induction relative to controls (Bgn+/+MRL) (normalized to Gapdh). (C and D) Western blots for active caspase-1 in kidneys from (C) 10-, 16-, and 24-week-old Bgn–/–MRL/lpr versus age-matched Bgn+/+MRL/lpr mice and from (D) 10-week-old Bgn+/+MRL and Bgn+/+MRL/lpr mice transiently transfected with hBGN, empty-vector– (pLIVE) and control solvent-injected mice normalized to β-tubulin and (E) quantified for 3 independent experiments. As there were no genotypic or age-dependent (10–24 weeks) differences in renal expression of pro-Il1B (A) and Nlrp3 (B), levels of active caspase-1 (C–E), and mature IL-1β (F), only results from 10- (A, B, and D–F) and 24-week-old (C) Bgn+/+MRL mice were used as controls. Data are given as mean ± SD. Asterisks indicate statistical significance; n = 6 (A, B, and F) and n = 3 (E). *P < 0.05.

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