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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 120 Issue 12 Pg. 4251-72 (Dec 2010) ISSN: 1558-8238 [Electronic] United States
• PMID: 21084753 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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