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

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 5

Effects of biglycan deficiency and overexpression on renal histopathology of lupus prone mice and their respective controls.

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Effects of biglycan deficiency and overexpression on renal histopatholog...
(A) PAS-stained kidney sections showing glomeruli (upper panels) and tubulointerstitium (lower panels) from 10-week-old Bgn+/+MRL, Bgn+/+MRL/lpr, Bgn–/–MRL/lpr, and biglycan-overexpressing (hBGN) mice and their respective controls as well as from 24-week-old Bgn–/–MRL/lpr and Bgn+/+MRL/lpr mice. There was no difference in renal histology between Bgn+/+MRL and Bgn–/–MRL mice. 24-week-old Bgn+/+MRL is shown as a control. The arrows indicate perivascular areas of infiltrating cells. Scale bars indicate the respective magnifications. (B) Quantification of the renal histological lesion score in 10-week-old hBGNBgn+/+MRL and hBGNBgn+/+MRL/lpr mice and their respective controls (pLIVE and solvent injected) and in 10-, 16-, and 24-week-old Bgn–/–MRL/lpr and Bgn+/+MRL/lpr mice. The renal lesion scores of at least 6 mice of each group were graded as described in Methods. Data are given as mean ± SD. Asterisks indicate statistical significance; n = 6. *P < 0.05.