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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 1

Overexpression of biglycan in the plasma and kidneys of patients suffering from LN.

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Overexpression of biglycan in the plasma and kidneys of patients sufferi...
(A) Immunoblots for biglycan protein core after semipurification of 0.2 ml plasma from healthy controls (Cont) and patients with class IV LN followed by chondroitinase ABC digestion. To standardize the assay, 0.3 μg of intact biglycan (containing protein core and glycosaminoglycan chains) was added to plasma samples from a healthy control (Cont. 0.3) and a LN patient (LN 0.3) prior to semipurification. All samples were purified simultaneously and under the same conditions. Standard (St) contained 0.3 μg of biglycan that was digested with chondroitinase ABC only. (B) Semiquantification of plasma biglycan calculated with consideration of assay recovery. The net biglycan gain was calculated by subtracting the control’s band intensity from that of Cont 0.3, or LN from LN 0.3, and expressed as a percentage of optical density as denominated by standard. Data are given as mean ± SD. *P < 0.05. (C and D) Correlations between levels of plasma biglycan and albuminuria (C) or plasma CXCL13 (D) in individuals with LN versus healthy controls. (E–J) Immunostaining for biglycan (APAAP, red color) in renal sections from LN patients (E–G) and healthy controls (H and I). Insert (G) shows a magnified view of an area with infiltrating mononuclear cells positive for biglycan. Counterstaining was done with Meyer’s hematoxylin. The negative control (J) was performed in renal sections from LN patients by using an antigen-preadsorbed (human biglycan) antiserum. Scale bars indicate the respective magnifications.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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