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Updated: Nov 26, 2025

Advanced Glycation End-Products Sensitize Human Sensory-Like Neuron Cells to Capsaicin-Induced Calcium Influx
Published on: May 2, 2025
The receptor for advanced glycation end products is a sensor for cell-free heme
Olivia May1,2,3, Laure Yatime4, Nicolas S Merle3
1Inserm, Institut Pasteur de Lille, U1167 - RID-AGE, Univ. Lille, France.
Abstract:
Heme's interaction with Toll-like receptor 4 (TLR4) does not fully explain the proinflammatory properties of this hemoglobin-derived molecule during intravascular hemolysis. The receptor for advanced glycation end products (RAGE) shares many features with TLR4 such as common ligands and proinflammatory, prothrombotic, and pro-oxidative signaling pathways, prompting us to study its involvement as a heme sensor. Stable RAGE-heme complexes with micromolar affinity were detected as heme-mediated RAGE oligomerization. The heme-binding site was located in the V domain of RAGE. This interaction was Fe3+ -dependent and competitive with carboxymethyllysine, another RAGE ligand. We confirmed a strong basal gene expression of RAGE in mouse lungs. After intraperitoneal heme injection, pulmonary TNF-α, IL1β, and tissue factor gene expression levels increased in WT mice but were significantly lower in their RAGE-/- littermates. This may be related to the lower activation of ERK1/2 and Akt observed in the lungs of heme-treated, RAGE-/- mice. Overall, heme binds to RAGE with micromolar affinity and could promote proinflammatory and prothrombotic signaling in vivo, suggesting that this interaction could be implicated in heme-overload conditions.
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