Lipopolysaccharide from Gut Microbiota Contributes to Pathogenesis of Murine Lupus Nephritis

Abstract

Background: Bacterial products from the gut may enter the circulation and induce inflammatory responses at distant sites, and gut microbiota has been implicated in the pathogenesis of autoimmune diseases. Lipopolysaccharide (LPS) is a component of the outer wall of Gram-negative bacteria. We previously showed that lupus nephritis patients had higher circulating LPS levels compared with healthy subjects. We investigated the role of LPS in the pathogenesis of murine lupus nephritis Methods: NZB/W F1 mice at 16-wk were randomized to receive saline or LPS (0.5 mg/kg body weight) once daily for 4 weeks, and their renal and colonic histopathology was examined. Intestinal mucosal permeability was investigated with LPS-FITC. Expression of LPS-binding protein (LBP), CD14 and TLR-4 was investigated with cytochemistry. Results: Serum LPS level was significantly higher in NZB/W F1 mice with active nephritis compared with age-matched BALB/c mice (P<0.05). Histopathologic features of active nephritis in NZB/W F1 mice were accompanied by increased LBP, CD14 and TLR-4 expression in proximal renal tubular epithelial cells. Mice with active nephritis also showed increased gut permeability, with orally fed LPS-FITC detected in renal proximal tubules. NZB/W F1 mice that received LPS showed increased proteinuria, and increased IgG and collagen deposition in glomeruli, compared with controls that received saline. Mice given LPS also showed decreased neutral mucin expression in goblet cells, and reduced ZO-1 and LBP expression, in the colonic epithelium, and also increased α-smooth muscle actin expression in the lamina propria. Conclusions: The data demonstrate that active murine lupus nephritis is associated with increased circulating LPS likely of gut origin, which may contribute to the pathogenesis of renal histopathologic features.