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

J Clin Invest. 2010 Dec;120(12):4251-72. doi: 10.1172/JCI42213. Epub 2010 Nov 15.


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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Animals
  • B-Lymphocytes / immunology
  • B-Lymphocytes / pathology
  • Biglycan / blood
  • Biglycan / deficiency
  • Biglycan / genetics
  • Biglycan / metabolism*
  • Case-Control Studies
  • Chemokine CXCL13 / blood
  • Chemokine CXCL13 / metabolism*
  • Chemokines / blood
  • Cytokines / blood
  • Diabetic Nephropathies / immunology
  • Diabetic Nephropathies / metabolism
  • Diabetic Nephropathies / pathology
  • Female
  • Graft Rejection / immunology
  • Graft Rejection / pathology
  • Humans
  • Kidney / immunology
  • Kidney / metabolism
  • Kidney / pathology
  • Lupus Erythematosus, Systemic / immunology
  • Lupus Erythematosus, Systemic / metabolism
  • Lupus Erythematosus, Systemic / pathology
  • Lupus Nephritis / immunology*
  • Lupus Nephritis / metabolism*
  • Lupus Nephritis / pathology
  • Macrophages / immunology
  • Macrophages / pathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred MRL lpr
  • Mice, Inbred NZB
  • Mice, Knockout
  • T-Lymphocytes / immunology
  • T-Lymphocytes / pathology
  • Toll-Like Receptor 2 / metabolism
  • Toll-Like Receptor 4 / metabolism
  • Young Adult


  • BGN protein, human
  • Bgn protein, mouse
  • Biglycan
  • CXCL13 protein, human
  • Chemokine CXCL13
  • Chemokines
  • Cxcl13 protein, mouse
  • Cytokines
  • Tlr2 protein, mouse
  • Tlr4 protein, mouse
  • Toll-Like Receptor 2
  • Toll-Like Receptor 4