Receptor for advanced glycation endproducts (RAGE) is a key regulator of oval cell activation and inflammation-associated liver carcinogenesis in mice

Abstract

The receptor for advanced glycation endproducts (RAGE) is a multiligand receptor and member of the immunoglobulin superfamily. RAGE is mainly involved in tissue damage and chronic inflammatory disorders, sustaining the inflammatory response upon engagement with damage-associated molecular pattern molecules (DAMPs) such as S100 proteins and high-mobility group box 1 (HMGB1). Enhanced expression of RAGE and its ligands has been demonstrated in distinct tumors and several studies support its crucial role in tumor progression and metastasis by still unknown mechanisms. Here we show that RAGE supports hepatocellular carcinoma (HCC) formation in the Mdr2 2/2 mouse model, a prototype model of inflammation-driven HCC formation, which mimics the human pathology. Mdr2 2/2 Rage 2/2 (dKO) mice developed smaller and fewer HCCs than Mdr2 2/2 mice. Interestingly, although in preneoplastic Mdr2 2/2 livers RAGE ablation did not affect the onset of inflammation, premalignant dKO livers showed reduced liver damage and fibrosis, in association with decreased oval cell activation. Oval cells expressed high RAGE levels and displayed reduced proliferation upon RAGE silencing. Moreover, stimulation of oval cells with HMGB1 promoted an ERK1/2-Cyclin D1-dependent oval cell proliferation in vitro. Finally, genetic and pharmacologic blockade of RAGE signaling impaired oval cell activation in an independent mouse model of oval cell activation, the choline deficient ethionine-supplemented dietary regime. Conclusion: Our data identified a novel function of RAGE in regulating oval cell activation and tumor development in inflammation-associated liver carcinogenesis. (HEPATOLOGY 2013; 58:363-373)

The HMGB1/RAGE axis triggers neutrophil-mediated injury amplification following necrosis

“…into lethally irradiated (2 × 6 Gy) recipients. Successful BMT in RAGE chimeric mice was confirmed via GFP fluorescence as described (55), taking advantage of GFP expression in Ager -/-mice. Successful BMT in Elane chimeric mice was confirmed by quantitative PCR (qPCR) in spleens.…”

In Vivo Implanted Bone Marrow-Derived Mesenchymal Stem Cells Trigger a Cascade of Cellular Events Leading to the Formation of an Ectopic Bone Regenerative Niche

“…In particular, the relative MFI associated with CD51, CD206, and receptor for advanced glycation end products (RAGE) were significantly increased in cell-seeded implants. In particular, RAGE is known to be involved in tissue damage and chronic inflammatory disorders, and to sustain the inflammatory response upon engagement with damage associated molecular pattern molecules (DAMPs), such as high mobility group box 1 (HMGB1) [15]. At the last considered time (day 7 after implantation), we observed a general reduction in the expression of all macrophage-specific markers, although the cell surface antigen CD86, associated with the M1 phenotype, remained significantly more expressed by host cells extracted from empty scaffolds, whereas the cell surface antigens CD206 and CD51, associated with the M2 profile, were still significantly more expressed by cells recovered from MSC-seeded scaffolds (Supplementary Fig.…”

Lineage fate of ductular reactions in liver injury and carcinogenesis

“…-/-animals are widely used as a genetic model for spontaneous, inflammation-induced HCC development (38,39), with extensive activation of progenitors that might undergo malignant transformation. Four of six animals analyzed at 12 months had developed tumor nodules (mean 4.0 ± 3.1).…”