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 2

Overexpression of biglycan in the plasma and kidneys from lupus-prone mice (Bgn+/+MRL/lpr).

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Overexpression of biglycan in the plasma and kidneys from lupus-prone mi...
(A and C) Immunoblots for biglycan protein core after semipurification from plasma (150 μl) (A) and kidneys (150 μg) (C) from Bgn+/+MRL/lpr mice with progressive LN versus Bgn+/+MRL control mice. Biglycan protein core (0.3 μg, A, or 0.1 μg, C) was used as standard. (B) Enhanced biglycan mRNA expression in kidneys from 10-, 16-, 20-, and 24-week-old Bgn+/+MRL/lpr mice versus the respective Bgn+/+MRL controls quantitated by TaqMan analysis after normalization to Gapdh (given as mean ± SD). Asterisks indicate statistical significance; n = 6. *P < 0.05. There was no age-dependent (10–24 weeks) difference in plasma levels (A), renal mRNA (B), and protein (C) expression of biglycan in MRL mice; therefore, only 1 time point is shown for the MRL controls. (D) Immunohistochemical analysis of biglycan expression patterns (APAAP, red) in the tubulointerstitium (upper panels) and glomeruli (lower panels) of renal tissue sections from 16-week-old control (Bgn+/+MRL) and 10- and 16-week-old Bgn+/+MRL/lpr mice. Counterstaining was done with Meyer’s hematoxylin. The negative control was performed in renal tissue sections from 16-week-old Bgn+/+MRL/lpr mice by preadsorption of anti-biglycan antibody with purified mouse biglycan prior to the incubation with renal sections. Scale bars: 100 μm.