Toll-like receptor 4 and Receptor for Advanced Glycation End-products signaling axis (TLR4/RAGE axis)

The TLR4/RAGE signaling axis is a synergistic pathway involving Toll-like receptor 4 (UniProt: O00206) and the Receptor for Advanced Glycation End-products (UniProt: Q15109) [1, 2]. These receptors are key components of the innate immune system and recognize a variety of endogenous ligands known as Damage-Associated Molecular Patterns (DAMPs) [3]. Common ligands like HMGB1 and S100 proteins can bind to both receptors, triggering a robust inflammatory response [3, 4]. Activation of this axis leads to the recruitment of adapter proteins like MyD88 and the subsequent activation of the NF-κB and MAPK pathways [4]. This signaling cascade results in the overproduction of pro-inflammatory cytokines, contributing to chronic inflammation and tissue damage [3]. The TLR4/RAGE axis is heavily implicated in the pathogenesis of sepsis, diabetic complications, and neurodegenerative disorders [4, 5]. Pharmacological targeting of this axis aims to disrupt the feed-forward loop of inflammation by using receptor antagonists or ligand-neutralizing agents [5]. Clinical candidates like Azeliragon have been explored for Alzheimer's disease, while TLR4 inhibitors like TAK-242 have been studied for sepsis [5, 6]. References: [1] UniProt O00206; [2] UniProt Q15109; [3] Andersson U, Tracey KJ. Annu Rev Immunol. 2011;29:139-62; [4] Iori V, et al. Front Immunol. 2017;8:1011; [5] Galasko D, et al. Alzheimers Dement. 2014;10(4):P274; [6] Rice TW, et al. Crit Care Med. 2010;38(12):2285-94.

Other names

TLR4-RAGE crosstalkTLR4/RAGE signaling pathwayHMGB1-TLR4-RAGE axisAGER-TLR4 axis

Antagonism of TLR4 or RAGE receptors, or sequestration of shared ligands such as HMGB1, to inhibit downstream pro-inflammatory signaling cascades like NF-κB and MAPK.