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 12

A working model summarizing the concept of biglycan-driven, CXCL13-mediated, and B cell–based inflammation in LN.

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A working model summarizing the concept of biglycan-driven, CXCL13-media...
Soluble biglycan acts as an endogenous danger signal in the kidney and triggers the expression of the B cell chemoattractant CXCL13 by signaling through TLR2 and TLR4 in interstitial macrophages and dendritic cells. Elevated levels of CXCL13 will result in recruitment of CXCR5-positive B cells, preferentially the B1 subset (B1) into the kidney. To further boost the inflammatory response, biglycan induces the synthesis of RANTES, MCP-1, and MIP-1α in macrophages, thereby attracting T cells (T) and additional macrophages along an increasing gradient of chemoattractants. In consequence, lymph follicle–like clusters of B cells, T cells, and macrophages develop in the kidney. Furthermore, biglycan triggers the expression of pro-Il1B mRNA via TLR2/4 in macrophages. By clustering TLR2/4 with P2X7R, biglycan stimulates inflammasome-dependent IL-1β maturation via ASC and caspase-1 (left lower panel). However, P2X7R and the inflammasome are not contributing to the regulation of CXCL13 expression. Excessive activation and recruitment of lymphocytes followed by further cytokine/chemokine secretion and antibody production by B lymphocytes will cause progressive inflammatory damage to the kidney. CS/DS, chondroitin/dermatan sulfate side chains.