Figure 2. Schematic diagram of the RAGE-ligands release, inflammatory responses and feedback mechanism in RAGE ligands/RAGE/sRAGE system after injury induced by acetaminophen overdose.

(1) Highly toxic metabolites produced by acetaminophen induce initial cell death resulting in diverse “danger” molecules including HMGB1, which, probably in conjunction with other inflammatory mediators, activate RAGE signaling on hepatic cells and/or dendritic cells and inflammatory cells. Ligand – RAGE interaction can lead to the activation of the MAPK pathways and the translocation of the transcription factor NF-κB from the cytosol to the nucleus, resulting in the up-regulation of genes involved in cellular inflammatory responses. (2) Then, these mediators, in an autocrine or paracrine manner, lead to receptor‐triggered transcriptional pathways resulting in the production of further pro-inflammatory mediator substances to create full‐scale tissue inflammation.

(3) Although the exact mechanisms are still unclear, plausibly high levels of sRAGE are part of a counter – regulatory mechanism elicited by inflammation/injury and other pathological situations, such as renal failure that enhancing the expression of RAGE and its ligands, result in increased accumulation of sRAGE as a negative feedback on RAGE interactions with its ligands (4).