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

• Published in: The Journal of clinical investigation Vol. 120; no. 12; pp. 4251 - 4272
• Main Authors: Moreth, Kristin, Brodbeck, Rebekka, Babelova, Andrea, Gretz, Norbert, Spieker, Tilmann, Zeng-Brouwers, Jinyang, Pfeilschifter, Josef, Young, Marian F, Schaefer, Roland M, Schaefer, Liliana
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.12.2010
• Subjects: Adolescent; Adult; Animals; Antigens; B cells; B-Lymphocytes - immunology; B-Lymphocytes - pathology; Biglycan - blood; Biglycan - deficiency; Biglycan - genetics; Biglycan - metabolism; Biomedical research; Case-Control Studies; Chemokine CXCL13 - blood; Chemokine CXCL13 - metabolism; Chemokines; Chemokines - blood; Cytokines - blood; Dendritic cells; Diabetic Nephropathies - immunology; Diabetic Nephropathies - metabolism; Diabetic Nephropathies - pathology; Disease; Female; Gene expression; Genetic aspects; Graft Rejection - immunology; Graft Rejection - pathology; Humans; Kidney - immunology; Kidney - metabolism; Kidney - pathology; Kidneys; Ligands; Lupus; Lupus Erythematosus, Systemic - immunology; Lupus Erythematosus, Systemic - metabolism; Lupus Erythematosus, Systemic - pathology; Lupus Nephritis - immunology; Lupus Nephritis - metabolism; Lupus Nephritis - pathology; Lymphocytes; Macrophages - immunology; Macrophages - pathology; Male; Mice; Mice, Inbred C57BL; Mice, Inbred MRL lpr; Mice, Inbred NZB; Mice, Knockout; Nephritis; Pathogenesis; Pathogens; Physiological aspects; Plasma; Properties; Proteins; Proteoglycans; T-Lymphocytes - immunology; T-Lymphocytes - pathology; Toll-Like Receptor 2 - metabolism; Toll-Like Receptor 4 - metabolism; Young Adult; Germany
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci42213

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.