Regulation of TLR9 dependent DNA Immune complex mediated cell activation by High Mobility Group Box Protein 1 (HMGB1) and Receptor for Advanced Glycation End products (RAGE) (128.35)

Abstract

Abstract Stimulation of endosomal associated TLR9 by DNA plays an important role in activation of plasmacytoid dendritic cells (pDCs) and autoreactive B cells and may contribute to the pathogenesis of systemic lupus erythematosus (SLE). HMGB1 is a DNA binding protein that is liberated either from cells undergoing necrosis or following cytokine stimulation. Here we show that HMGB1 forms a high affinity complex with CpG-A oligodeoxynucleotides and augments the production of IFN-a from murine pDCs. We also show that HMGB1 is indeed a component of naturally formed DNA containing chromatin complexes. IFNa induced by either the exogenously formed HMGB1/CpG-A complex or naturally formed complex is TLR9 dependent and is inhibited by HMGB1 and RAGE antagonists. The complex without HMGB1 induces significantly less IFNa. HMGB1-RAGE interactions are required for activation of autoreactive B cells following stimulation with DNA immune complexes and are critical in the regulation of type I interferon gene induction by DNA complexes present in lupus plasma. Our data provide a novel mechanism by which HMGB1 confers potent stimulatory activity to DNA through a RAGE dependent mechanism and may contribute to the pathogenesis of lupus.