| First Author | May O | Year | 2021 |
| Journal | FEBS J | Volume | 288 |
| Issue | 11 | Pages | 3448-3464 |
| PubMed ID | 33314778 | Mgi Jnum | J:329817 |
| Mgi Id | MGI:7344208 | Doi | 10.1111/febs.15667 |
| Citation | May O, et al. (2021) The receptor for advanced glycation end products is a sensor for cell-free heme. FEBS J 288(11):3448-3464 |
| abstractText | 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 Fe(3+) -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-alpha, IL1beta, 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. |
