Insights into the molecular basis and mechanism of heme‐triggered TLR4 signalling: The role of heme‐binding motifs in TLR4 and MD2 DOI Creative Commons
Marie-Thérèse Hopp,

Janine Holze,

Felicitas Lauber

et al.

Immunology, Journal Year: 2023, Volume and Issue: 171(2), P. 181 - 197

Published: Oct. 26, 2023

Abstract Haemolytic disorders, such as sickle cell disease, are accompanied by the release of high amounts labile heme into intravascular compartment resulting in induction proinflammatory and prothrombotic complications affected patients. In addition to relevance heme‐regulated proteins from complement blood coagulation systems, activation TLR4 signalling pathway was ascribed a crucial role progression these pathological processes. Heme binding TLR4‐MD2 complex has been proposed recently, however, essential mechanistic information processes at molecular level, heme‐binding kinetics, capacity respective sites (HBMs) is still missing. We report interaction TLR4, MD2 with consequences thereof employing biochemical, spectroscopic, bioinformatic physiologically relevant approaches. occurs transiently through up four HBMs two least their complex. Functional studies highlight that mutations individual preserve full receptor heme, suggesting interacts different independently MD2. Furthermore, we confirm extend major for heme‐mediated cytokine responses human immune cells.

Language: Английский

Heme Interferes With Complement Factor I-Dependent Regulation by Enhancing Alternative Pathway Activation DOI Creative Commons
Alexandra Gerogianni, Jordan D. Dimitrov, Alessandra Zarantonello

et al.

Frontiers in Immunology, Journal Year: 2022, Volume and Issue: 13

Published: July 22, 2022

Hemolysis, as a result of disease or exposure to biomaterials, is characterized by excess amounts cell-free heme intravascularly and consumption the protective heme-scavenger proteins in plasma. The liberation has been linked activation inflammatory systems, including complement system, through alternative pathway activation. Here, we investigated impact on regulatory function system. Heme dose-dependently inhibited factor I-mediated degradation soluble surface-bound C3b, when incubated plasma buffer with proteins. Inhibition occurred H receptor 1 co-factors, mechanism was direct heme-interaction I. protein hemopexin main contaminant purified I preparations. This led us identify that formed complex normal human These complexes were significantly reduced during acute vasoocclusive pain crisis patients sickle cell disease, but normalized at their baseline outpatient clinic visit. Hemopexin exposed activity vitro , only it present before addition heme. In conclusion, mechanistic explanation how promotes uncontrolled amplification interfering capacity Reduced levels hemopexin-factor an hemolytic risk for heme-mediated inhibition.

Language: Английский

Citations

17
Diffuse right coronary artery spasm occurring forty-five minutes post pulsed field ablation for atrial fibrillation DOI Creative Commons
Vishal Luther, Justin Chiong,

Catherine James

et al.

Heart Rhythm, Journal Year: 2025, Volume and Issue: unknown

Published: March 1, 2025

Language: Английский

Citations

0
Hemopexin as an Inhibitor of Hemolysis-Induced Complement Activation DOI Creative Commons
Victoria Poillerat, Thomas Gentinetta, Juliette Léon

et al.

Frontiers in Immunology, Journal Year: 2020, Volume and Issue: 11

Published: July 31, 2020

Hemopexin is the main plasmatic scavenger of cell-free heme, released in context intravascular hemolysis or major cell injury. Heme indispensable for oxygen transport by hemoglobin but when outside erythrocytes it becomes a danger-associated molecular pattern, contributing to tissue One mechanisms pro-inflammatory action heme activate innate immune complement cascade. Therefore, we hypothesized that injection hemopexin will prevent hemolysis-induced activation. Human plasma-derived compatible with clearance machinery mice. 100 500 mg/kg was injected C57Bl/6 mice before treatment phenylhydrazine (inducer lysis) PBS as control. Blood taken at different timepoints determine pharmacokinetic presence and absence hemolysis. Complement activation determined plasma, C3 cleavage (western blot) kidneys (immunofluorescence). Kidney injury evaluated urea creatinine plasma renal NGAL HO-1 gene expression were measured. The properties (mass spectrometry) hemolytic affected target-mediated drug disposition phenomenon due high affinity binding heme. Hemolysis induced overactivation signs mild dysfunction 6h, which prevented hemopexin, except upregulation. heme-degrading capacity kidney, measured expression, not treatment. These results encourage further studies therapeutic agent models diseases overload.

Language: Английский

Citations

25
The receptor for advanced glycation end products is a sensor for cell‐free heme DOI Open Access
Olivia May, Laure Yatime, Nicolas S. Merle

et al.

FEBS Journal, Journal Year: 2020, Volume and Issue: 288(11), P. 3448 - 3464

Published: Dec. 12, 2020

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 for advanced glycation end products (RAGE) shares many features TLR4 such as common ligands and proinflammatory, prothrombotic, pro-oxidative signaling pathways, prompting us to study its involvement a heme sensor. Stable RAGE-heme complexes micromolar affinity were detected heme-mediated RAGE oligomerization. heme-binding site was located in V domain RAGE. This Fe3+ -dependent competitive carboxymethyllysine, another ligand. We confirmed strong basal gene expression mouse lungs. After intraperitoneal injection, pulmonary TNF-α, IL1β, tissue factor levels increased WT mice but significantly lower their RAGE-/- littermates. may be related activation ERK1/2 Akt observed lungs heme-treated, mice. Overall, binds could promote prothrombotic vivo, suggesting that implicated heme-overload conditions.

Language: Английский

Citations

24
Insights into the molecular basis and mechanism of heme‐triggered TLR4 signalling: The role of heme‐binding motifs in TLR4 and MD2 DOI Creative Commons
Marie-Thérèse Hopp,

Janine Holze,

Felicitas Lauber

et al.

Immunology, Journal Year: 2023, Volume and Issue: 171(2), P. 181 - 197

Published: Oct. 26, 2023

Abstract Haemolytic disorders, such as sickle cell disease, are accompanied by the release of high amounts labile heme into intravascular compartment resulting in induction proinflammatory and prothrombotic complications affected patients. In addition to relevance heme‐regulated proteins from complement blood coagulation systems, activation TLR4 signalling pathway was ascribed a crucial role progression these pathological processes. Heme binding TLR4‐MD2 complex has been proposed recently, however, essential mechanistic information processes at molecular level, heme‐binding kinetics, capacity respective sites (HBMs) is still missing. We report interaction TLR4, MD2 with consequences thereof employing biochemical, spectroscopic, bioinformatic physiologically relevant approaches. occurs transiently through up four HBMs two least their complex. Functional studies highlight that mutations individual preserve full receptor heme, suggesting interacts different independently MD2. Furthermore, we confirm extend major for heme‐mediated cytokine responses human immune cells.

Language: Английский

Citations

9