title: 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.affiliation: 1Pharmazentrum Frankfurt, Institut für Allgemeine Pharmakologie und Toxikologie/ZAFES, Klinikum der JW Goethe-Universität Frankfurt am Main, Frankfurt am Main, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Moreth
authors.forename: Rebekka
authors.initials: R
authors.lastname: Brodbeck
authors.forename: Andrea
authors.initials: A
authors.lastname: Babelova
authors.forename: Norbert
authors.initials: N
authors.lastname: Gretz
authors.forename: Tilmann
authors.initials: T
authors.lastname: Spieker
authors.forename: Jinyang
authors.initials: J
authors.lastname: Zeng-Brouwers
authors.forename: Josef
authors.initials: J
authors.lastname: Pfeilschifter
authors.forename: Marian F
authors.initials: MF
authors.lastname: Young
authors.forename: Roland M
authors.initials: RM
authors.lastname: Schaefer
authors.forename: Liliana
authors.initials: L
authors.lastname: Schaefer
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D058578:Biglycan / Q000097:blood / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D054382:Chemokine CXCL13 / Q000097:blood / Q000378:metabolism*; D018925:Chemokines / Q000097:blood; D016207:Cytokines / Q000097:blood; D003928:Diabetic Nephropathies / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005260:Female; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology; D006801:Humans; D007668:Kidney / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008181:Lupus Nephritis / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D008814:Mice, Inbred NZB; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D055815:Young Adult
chemical_list: C546884:BGN protein, human; C546885:Bgn protein, mouse; D058578:Biglycan; C110663:CXCL13 protein, human; D054382:Chemokine CXCL13; D018925:Chemokines; C486386:Cxcl13 protein, mouse; D016207:Cytokines; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4