High mobility group box 1-Advanced glycosylation end product-specific receptor signaling axis (HMGB1-RAGE axis)

The High mobility group box 1 (HMGB1)-Advanced glycosylation end product-specific receptor (RAGE) signaling axis is a pivotal mediator of the sterile inflammatory response and tissue homeostasis (UniProt P09429, Q15109). HMGB1, originally identified as a non-histone nuclear DNA-binding protein, acts as a prototypical damage-associated molecular pattern (DAMP) when secreted or passively released by necrotic cells (PubMed: 28933098). Upon binding to RAGE, it initiates robust intracellular signaling through the NF-κB and MAPK pathways, leading to the expression of pro-inflammatory cytokines and adhesion molecules (PubMed: 31434157). This axis plays a significant role in the pathogenesis of diverse conditions, including sepsis, rheumatoid arthritis, and various malignancies where it promotes tumor cell invasion and metastasis (PubMed: 23554310). Therapeutic targeting of this axis involves the use of small molecule RAGE antagonists like Azeliragon or HMGB1-neutralizing agents like Glycyrrhizin to dampen chronic inflammation (PubMed: 29241441). However, challenges remain due to the multi-ligand nature of RAGE and the essential physiological roles of HMGB1 in DNA repair and stability.

Other names

HMGB1-AGER axisAmphoterin-RAGE pathwayHigh mobility group protein B1-RAGE signaling

The primary mechanism involves the competitive or non-competitive inhibition of the binding between extracellular HMGB1 and the V-domain of RAGE, thereby preventing the recruitment of adapter proteins like TIRAP and MyD88 and subsequent activation of pro-inflammatory transcription factors (PubMed: 28933098).