Immune complexes activate human endothelium involving the cell-signaling HMGB1-RAGE axis in the pathogenesis of lupus vasculitis

Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the formation of immune complexes (ICs), which contain a complex mixture of autoantigens nucleic acids, nucleic acids-associated proteins and corresponding autoantibodies. In SLE, ICs are deposited in multiple organs. Vasculopathy and vasculitis in SLE are typical complications and are associated with deposition of ICs on endothelium, endothelial activation and inflammatory cell infiltration. However, the effects of ICs on endothelial cells and the mechanisms involved remain unclear. In this study, we have demonstrated for the first time that ICs upregulated cell surface expression of the receptor for advanced glycation end products (RAGE), the expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), increased the secretion of the chemokines interleukin 8 (IL-8), monocyte chemoattractant protein-1 (MCP-1), the proinflammatoy cytokines interleukin 6 (IL-6), tumor necrosis factor-a (TNF-a) and promoted the activation of the transcription factor NF-kB p65 in human endothelial cells (Po0.05). ICs also increased transendothelial migration of monocytes (Po0.05). One of the mechanisms underlying these activating effects of ICs on human endothelial cells involves cell signaling by high-mobility group box 1 protein (HMGB1)-RAGE axis, as these effects can be partially blocked by HMGB1 A-box, soluble RAGE (sRAGE), SB203580, PD98059, Bay 117082 (Po0.05) and co-treatment with these agents (Po0.05). In conclusion, ICs elicit proinflammatory responses in human endothelial cells and alter their function involving cellular signaling via the HMGB1-RAGE axis in the pathogenesis of SLE vasculitis.

The Role of HMGB1 in the Pathogenesis of Inflammatory and Autoimmune Diseases

“…Interestingly, in this model, autoantibody production involves TLR2, one of the receptors for HMGB1. In addition to these activities, complexes can also interact with RAGE on endothelium to create the vasculopathy that marks the course of SLE (63).…”

Immune Monitoring of Trans-endothelial Transport by Kidney-Resident Macrophages

“…However, low molecular weight immune complexes (referred to below as small immune complexes, SIC) are believed to be less efficiently cleared by liver and spleen macrophages, which can result in the activation of neutrophils and monocytes (Jancar and Crespo; Jönsson et al, 2013; Mayadas et al, 2009), complement (Merle et al, 2015), endothelial cells (Sun et al, 2013) and mast cells (Daha et al, 1988). Immune complexes also deposit in tissues, either as a result of increased vascular permeability or tissue damage (Binstadt et al, 2006; Stokol et al, 2004).…”

Recent Developments in the Role of High-Mobility Group Box 1 in Systemic Lupus Erythematosus

“…Furthermore, incubating human monocyte-derived macrophages with HMGB1-nucleosome complexes induced cytokine production, which could be blocked by adding box A. Whereas these studies focused on effects of HMGB1 on lymphocytes, Sun et al (33) investigated the effect of HMGB1-containing immune complexes on human endothelial cells. They showed that stimulating endothelial cells with immune complexes from SLE patients increased proinflammatory cytokines such as IL-6 and IL-8.…”