Septic Shock Is Associated with Receptor for Advanced Glycation End Products Ligation of LPS

Abstract

Septic shock is a severe systemic response to bacterial infection. Receptor for advanced glycation end products (RAGE) plays a role in immune reactions to recognize specific molecular patterns as pathogen recognition receptors. However, the interaction between LPS, the bioactive component of bacterial cell walls, and RAGE is unclear. In this study, we found direct LPS binding to RAGE by a surface plasmon resonance assay, a plate competition assay, and flow cytometry. LPS increased TNF-α secretion from peritoneal macrophages and an NF-κB promoter-driven luciferase activity through RAGE. Blood neutrophils and monocytes expressed RAGE, and TLR2 was counterregulated in RAGE−/− mice. After LPS injection, RAGE+/+ mice showed a higher mortality, higher serum levels of IL-6, TNF-α, high mobility group box 1, and endothelin-1, and severe lung and liver pathologies compared with RAGE−/− mice without significant differences in plasma LPS level. Administration of soluble RAGE significantly reduced the LPS-induced cytokine release and tissue damage and improved the LPS-induced lethality even in RAGE−/− as well as RAGE+/+ mice. The results thus suggest that RAGE can associate with LPS and that RAGE system can regulate inflammatory responses. Soluble RAGE would be a therapeutic tool for LPS-induced septic shock.

RAGE-Mediated Suppression of Interleukin-10 Results in Enhanced Mortality in a Murine Model of Acinetobacter baumannii Sepsis

“…However, these findings are in contrast to the limited role of RAGE in a model of systemic infection caused by S. pneumoniae where RAGE did not alter multiple metrics of disease severity (21). RAGE is known to directly bind lipopolysaccharide of Gram-negative bacteria (36). Therefore, these discrepancies may result from RAGE-mediated amplification of maladaptive inflammation in response to systemic Gram-negative, but not Gram-positive, bacterial infection.…”

“…2). These findings are consistent with cecal ligation and puncture and LPS models of polymicrobial or endotoxic septic shock where RAGE potentiated inflammation and increased mortality (19,36). However, these findings are in contrast to the limited role of RAGE in a model of systemic infection caused by S. pneumoniae where RAGE did not alter multiple metrics of disease severity (21).…”

Increased Myeloid-Derived Suppressor Cells in Gastric Cancer Correlate with Cancer Stage and Plasma S100A8/A9 Proinflammatory Proteins

“…RAGE inhibitors (TTP4000) are now in clinical development for use in Alzheimer's patients (Transtech Pharma). Other strategies, including RAGE- IgG fusion proteins (53), anti-RAGE mAb (54), and recombinant soluble RAGE (55), have been used to inhibit RAGE signaling in preclinical models across other diseases. All of these strategies have focused on the ligand-RAGE interaction without any consideration for ligand specificity.…”

The receptor for advanced glycation end products mediates lung endothelial activation by RBCs

“…THE RECEPTOR FOR ADVANCED glycation end products (RAGE) is widely expressed on systemic endothelium and functions as a pattern recognition receptor for multiple ligands, including advanced glycation end products (AGEs), high mobility group box 1 (HMGB1), calgranulins (s100A12 and s100B), amyloid ␤-proteins, Mac-1, phosphotidylserine, and lipopolysaccharide (10,24,26,35). AGEs, a heterogenous group of adducts formed during pathological states, hyperglycemia, and periods of increased oxidative stress, lead to increased generation of reactive oxygen species (ROS) and inflammatory cytokines following ligation of RAGE expressed on vascular endothelium (25,31,32).…”