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.

Small leucine-rich proteoglycans orchestrate receptor crosstalk during inflammation

“…8,15 Lack of biglycan results in a marked reduction of TNFα and IL1β and of infiltrating mononuclear cells in these models. 8,15 These effects are NLRP3-and caspase-1-dependent.…”

“…acts as an endogenous ligand of TLR2 and TLR4 in macrophages and dendritic cells, resulting in rapid activation of p38, Erk and NFκB pathways and enhanced synthesis of proinflammatory TNFα 8,14,15 (Fig. 2).…”

“…2). Furthermore, biglycan-mediated signaling via TLR2/4 leads to the synthesis of various chemoattractants for neutrophils and macrophages, such as macrophage inflammatory protein-1α (MIP-1α), monocyte chemoattractant protein-1 (MCP-1) and regulated upon activation, normal T-cell expressed and secreted (RANTES) 8,14 (Fig. 2).…”

“…Several reports have addressed the role of receptor crosstalk linking innate and adaptive immunity. [7][8][9] In addition, microRNAs (miRs) have been shown to act as fine-tuners of the inflammatory response reaction. 10 Over the last few decades, much has been revealed about the mechanisms of pathogen-mediated inflammation.…”

A comparative evaluation of the small leucine-rich proteoglycans of pathological human intervertebral discs

“…Biglycan has been shown to trigger cell-mediated inflammation via its effect on chemokines and B cell activation and has been described as a multireceptor signalling complex. When the complex is activated it can lead to many other effects including caspase activation and generation of the cytokines, TNFa and IL-1b [20]. There is some evidence that fragments may be more potent in cell signalling than intact molecules [27].…”