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.

Oxytocin sets the stage for childbirth by initiating uterine contractions, lactation and maternal bonding behaviours. Mice lacking secreted oxcytocin (Oxt^−/−, Cd38^−/−) or its receptor (Oxtr^−/−) fail to nurture. Normal maternal behaviour is restored by peripheral oxcytocin replacement in Oxt^−/− and Cd38^−/−, but not Oxtr^−/− mice, implying that circulating oxcytocin crosses the blood-brain barrier. Exogenous oxcytocin also has behavioural effects in humans. However, circulating polypeptides are typically excluded from the brain. We show that oxcytocin is transported into the brain by receptor for advanced glycation end-products (RAGE) on brain capillary endothelial cells. The increases in oxcytocin in the brain which follow exogenous administration are lost in Ager^−/− male mice lacking RAGE, and behaviours characteristic to abnormalities in oxcytocin signalling are recapitulated in Ager^−/− mice, including deficits in maternal bonding and hyperactivity. Our findings show that RAGE-mediated transport is critical to the behavioural actions of oxcytocin associated with parenting and social bonding.

Obesity is associated with inflammation and type 2 diabetes. Innate immune system comprised of cellular and molecular components plays an important role in the inflammatory reactions. Immune cells like macrophages and their cell surface pattern-recognition receptors (PRRs) are representative for innate immunity promoting inflammatory reactions. The receptor for advanced glycation end-products (RAGE) is a member of PRRs and a proinflammatory molecular device that mediates danger signals to the body. The expression of RAGE is observed in adipocytes as well as immune cells, endothelial cells, and pancreatic β cells under certain conditions. It has been reported that RAGE is implicated in adipocyte hypertrophy and insulin resistance. RAGE-mediated regulation of adiposity and inflammation may attribute to type 2 diabetes and diabetic vascular complications.

Hepatocellular death increases with hepatic steatosis aggravation, although its regulation remains unclear. Here we show that hepatic steatosis aggravation shifts the hepatocellular death mode from apoptosis to necroptosis, causing increased hepatocellular death. Our results reveal that the transcription factor ATF3 acts as a master regulator in this shift by inducing expression of RIPK3, a regulator of necroptosis. In severe hepatic steatosis, after partial hepatectomy, hepatic ATF3-deficient or -overexpressing mice display decreased or increased RIPK3 expression and necroptosis, respectively. In cultured hepatocytes, ATF3 changes TNFα-dependent cell death mode from apoptosis to necroptosis, as revealed by live-cell imaging. In non-alcoholic steatohepatitis (NASH) mice, hepatic ATF3 deficiency suppresses RIPK3 expression and hepatocellular death. In human NASH, hepatocellular damage is correlated with the frequency of hepatocytes expressing ATF3 or RIPK3, which overlap frequently. ATF3-dependent RIPK3 induction, causing a modal shift of hepatocellular death, can be a therapeutic target for steatosis-induced liver damage, including NASH.

Diabetic angiopathy including micro- and macroangiopathy is concerned with high rate of morbidity and mortality in patients with long-standing diabetes. Receptor for advanced glycation end products (RAGE) and its ligands have been considered as important pathogenic triggers for the progression of the vascular injuries in diabetes. The deleterious link between RAGE and diabetic angiopathy has been demonstrated in animal studies. Preventive and therapeutic strategies focusing on RAGE and its ligand axis may be of great importance in relieving diabetic vascular complications and reducing the burden of disease.

The cell-surface RAGE [receptor for AGE (advanced glycation end-products)] is associated with the development of diabetic vascular complications, neurodegenerative disorders and inflammation. Recently, we isolated a human RAGE splice variant, which can work as a decoy receptor for RAGE ligands, and named it esRAGE (endogenous secretory RAGE). In the present study, we have isolated the murine equivalent of esRAGE from brain polysomal poly(A)⁺ (polyadenylated) RNA by RT (reverse transcription)–PCR cloning. The mRNA was generated by alternative splicing, and it encoded a 334-amino-acid protein with a signal sequence, but lacking the transmembrane domain. A transfection experiment revealed that the mRNA was actually translated as deduced to yield the secretory protein working as a decoy in AGE-induced NF-κB (nuclear factor κB) activation. RT–PCR and immunoblotting detected esRAGE mRNA and protein in the brain, lung, kidney and small intestine of wild-type mice, but not of RAGE-null mice. The esRAGE expression was increased in the kidney of diabetic wild-type mice. The present study has thus provided an animal orthologue of esRAGE for clarification of its roles in health and disease.