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

Targeting the Heme-Heme Oxygenase System to Prevent Severe Complications Following COVID-19 Infections DOI Creative Commons
Frank A. D. T. G. Wagener, Peter Pickkers, Stephen J. Peterson

et al.

Antioxidants, Journal Year: 2020, Volume and Issue: 9(6), P. 540 - 540

Published: June 19, 2020

SARS-CoV-2 is causing a pandemic resulting in high morbidity and mortality. COVID-19 patients suffering from acute respiratory distress syndrome (ARDS) are often critically ill show lung injury hemolysis. Heme prosthetic moiety crucial for the function of wide variety heme-proteins, including hemoglobin cytochromes. However, injury-derived free heme promotes adhesion molecule expression, leukocyte recruitment, vascular permeabilization, platelet activation, complement thrombosis, fibrosis. can be degraded by anti-inflammatory enzyme oxygenase (HO) generating biliverdin/bilirubin, iron/ferritin, carbon monoxide. We therefore postulate that contributes to many inflammatory phenomena witnessed patients, whilst induction HO-1 or harnessing may provide protection. HO-activity not only degrades injurious heme, but its effector molecules possess also potent salutary anti-oxidative properties. Until vaccine against becomes available, we need explore novel strategies attenuate pro-inflammatory, pro-thrombotic, pro-fibrotic consequences leading The heme-HO system represents an interesting target “proof concept” studies context COVID-19.

Language: Английский

Citations

80
Basic Mechanisms of Hemolysis-Associated Thrombo-Inflammation and Immune Dysregulation DOI
Jordan D. Dimitrov, Lubka T. Roumenina, Gina Perrella

et al.

Arteriosclerosis Thrombosis and Vascular Biology, Journal Year: 2023, Volume and Issue: 43(8), P. 1349 - 1361

Published: June 15, 2023

Independent of etiology, hemolytic diseases are associated with thrombosis, inflammation and immune dysregulation, all together contributing to organ damage poor outcome. Beyond anemia the loss anti-inflammatory functions red blood cells, hemolysis leads release damage-associated molecular patterns including ADP, hemoglobin, heme, which act through multiple receptors signaling pathways fostering a hyperinflammatory hypercoagulable state. Extracellular free heme is promiscuous alarmin capable triggering oxido-inflammatory thrombotic events by inducing activation platelets, endothelial innate cells as well coagulation complement cascades. In this review, we discuss main mechanisms and, in particular, drive thrombo-inflammatory milieu consequences on host response secondary infections.

Language: Английский

Citations

25
Nrf2/HO-1 as a therapeutic target in renal fibrosis DOI
Emad H. M. Hassanein, Islam M. Ibrahim,

Esraa K. Abd‐alhameed

et al.

Life Sciences, Journal Year: 2023, Volume and Issue: 334, P. 122209 - 122209

Published: Oct. 25, 2023

Language: Английский

Citations

24
Free Foetal Haemoglobin in Severe Early‐Onset Foetal Growth Restriction: A Prospective Multi‐Centre Study DOI Creative Commons

Adam Brook,

Georgia C. Baynes,

Jonathan Scargill

et al.

BJOG An International Journal of Obstetrics & Gynaecology, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 19, 2025

ABSTRACT Objective To assess foetal circulating free haemoglobin (fHbF) levels and heme defences, correlated to circulatory biometry sex in severe early‐onset growth restriction (FGR). Design, Setting Population A prospective study pregnancies with close clinical management (estimated weight (EFW) < 3rd centile 600 g at 20–26 + 6 weeks; N = 20). Method & Main Outcome Measures Temporal vascular obstetric was recorded. Cord blood fHbF key heme‐scavenger defences were measured compared normal term births ( 26) late‐onset FGR 12). Results elevated pregnancy: 0.437(0.337/0.753) mg/mL; 0.098 (0.045/0.264) mg/mL, respectively p 0.0001); whilst hemopexin downregulated early‐ 0.001) 0.0001), 36(14/81) μg/mL, 25(19/40) 155(132/219) respectively; median (interquartile ranges). Early‐onset male foetuses had higher HbF the males: 0.710(0.433/0.857) 0.001); 0.099(0.043/0.246) In FGR, ratios of mid‐cerebral artery umbilical pulsatility indices positively (hemopexin a heme‐handling composite measure: 0.05, r 0.672; 0.01, 0.620; respectively), indicating lower are associated cerebral redistribution. These handling measures also gestational age delivery 0.713 0.642, respectively, both) birthweight 0.742, 0.001; 0.523, 0.05; respectively). Conclusion Overproduction an inadequate defence may contribute distress poor arterial Dopplers early onset due placental resistance inflammation.

Language: Английский

Citations

1
Complement activation in sickle cell disease: Dependence on cell density, hemolysis and modulation by hydroxyurea therapy DOI Open Access
Lubka T. Roumenina, Philippe Chadebech,

Gwellaouen Bodivit

et al.

American Journal of Hematology, Journal Year: 2020, Volume and Issue: 95(5), P. 456 - 464

Published: Jan. 28, 2020

The complement system is an innate immune defense cascade that can cause tissue damage when inappropriately activated. Evidence for over activation has been reported in small cohorts of patients with sickle cell disease (SCD). However, the mechanism governing SCD not elucidated. Here, we observe plasma concentration sC5b-9, a reliable marker terminal activation, increased at steady state 61% untreated patients. We show greater vitro promoted by erythrocytes compared to normal ones, although no significant differences were observed regulatory proteins CD35, CD55, and CD59 whole blood. Complement positively correlated percentage dense cells (DRBCs). expression levels are reduced DRBCs, suggesting inefficient regulation density increases. Moreover, surface regulator CD46 on granulocytes was inversely sC5b-9. also deposition cultured human endothelial incubated serum, which diminished addition heme scavenger hemopexin. Treatment hydroxyurea produces substantial reductions measured sC5b-9 upregulation CD46, as well decreased RBCs vitro. In conclusion, common pathogenic event associated formation DRBCs hemolysis. And, it affects red cells, leukocytes cells. This partly alleviated therapy.

Language: Английский

Citations

59
Red Blood Cells and Hemoglobin in Human Atherosclerosis and Related Arterial Diseases DOI Open Access
Jean‐Baptiste Michel, José Luis Martı́n-Ventura

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(18), P. 6756 - 6756

Published: Sept. 15, 2020

As the main particulate component of circulating blood, RBCs play major roles in physiological hemodynamics and impact all arterial wall pathologies. are determinant blood viscosity, defining frictional forces exerted by on wall. This function is used phylogeny ontogeny cardiovascular (CV) system, allowing acquisition vasomotricity adapted to local metabolic demands, systemic pressure after birth. In pathology, collide with wall, inducing both retention their membranous lipids hemolysis, releasing heme-Fe++ a high toxicity for cells: endothelial smooth muscle cells (SMCs) cardiomyocytes, neurons, etc. Specifically, overloading Fe++ promotes cell death. hemolysis an event associated early advanced stages human atherosclerosis. Similarly, permanent renewal mural RBC clotting support oxidation abdominal aortic aneurysm. parallel, calcifications promote intramural hemorrhages, hemorrhages osteoblastic phenotypic shift cells. Different plasma or tissue systems able, at least part, limit this injury acting different levels system.

Language: Английский

Citations

56
Whole blood viscosity and red blood cell adhesion: Potential biomarkers for targeted and curative therapies in sickle cell disease DOI Creative Commons
Erdem Kucukal, Yuncheng Man, Ailis Hill

et al.

American Journal of Hematology, Journal Year: 2020, Volume and Issue: 95(11), P. 1246 - 1256

Published: July 13, 2020

Abstract Sickle cell disease (SCD) is a recessive genetic blood disorder exhibiting abnormal rheology. Polymerization of sickle hemoglobin, due to point mutation in the β‐globin gene results aberrantly adhesive and stiff red cells (RBCs). Hemolysis, RBC adhesion, rheology together impair endothelial health people with SCD, which leads cumulative systemic complications. Here, we describe microfluidic assay combined micro particle image velocimetry technique for integrated vitro assessment whole viscosity (WBV) adhesion. We examined WBV adhesion laminin (LN) microscale flow samples from 53 individuals no hemoglobinopathies (HbAA, N = 10), hemoglobin SC (HbSC, 14), or homozygous SCD (HbSS, 29) mean 4.50 cP, 4.08 3.73 respectively. found that correlated count hematocrit subjects HbSC HbSS. There was significant inverse association between under both normoxic physiologically hypoxic (SpO 2 83%) tests, lower associated higher LN Low has been by others associate activation. Altered may synergistically contribute damage pathophysiology SCD. These findings suggest serve as clinically relevant biomarkers endpoints assessing emerging targeted curative therapies

Language: Английский

Citations

54
Platelet activation and ferroptosis mediated NETosis drives heme induced pulmonary thrombosis DOI Creative Commons
Somanathapura K. NaveenKumar, Mahadevappa Hemshekhar,

Bidare N. SharathBabu

et al.

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, Journal Year: 2023, Volume and Issue: 1869(5), P. 166688 - 166688

Published: March 15, 2023

Language: Английский

Citations

20
Pregnancy as a susceptible state for thrombotic microangiopathies DOI Creative Commons
Marie Frimat, Viviane Gnemmi,

Morgane Stichelbout

et al.

Frontiers in Medicine, Journal Year: 2024, Volume and Issue: 11

Published: Feb. 27, 2024

Pregnancy and the postpartum period represent phases of heightened vulnerability to thrombotic microangiopathies (TMAs), as evidenced by distinct patterns pregnancy-specific TMAs (e.g., preeclampsia, HELLP syndrome), well a higher incidence nonspecific TMAs, such thrombocytopenic purpura or hemolytic uremic syndrome, during pregnancy. Significant strides have been taken in understanding underlying mechanisms these disorders past 40 years. This progress has involved identification pivotal factors contributing complement system, ADAMTS13, soluble VEGF receptor Flt1. Regardless specific causal factor (which is not generally unique relation usual multifactorial origin TMAs), endothelial cell stands central player pathophysiology TMAs. major impact on physiology endothelium. Besides development placenta its vascular consequences, pregnancy modifies characteristics women’s microvascular endothelium tends render it more prone thrombosis. review aims delineate features pregnancy-related explore that lead this increased susceptibility, particularly influenced “gravid endothelium.” Furthermore, we will discuss potential contribution histopathological studies facilitating etiological diagnosis

Language: Английский

Citations

7
TLR4 Signaling by Heme and the Role of Heme-Binding Blood Proteins DOI Creative Commons
Sabina Janciauskiene, Vijith Vijayan, Stephan Immenschuh

et al.

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

Published: Aug. 27, 2020

Toll-like receptors (TLRs), also known as pattern recognition receptors, respond to exogenous pathogens and intrinsic danger signals released from damaged cells tissues. More recently, heme has been suggested an agonist for TLR4, the receptor pro-inflammatory bacterial lipopolysaccharide (LPS). Heme is a double-edged sword with contradictory functions. On one hand, vital cellular functions prosthetic group of hemoproteins such hemoglobin, myoglobin cytochromes. other if destabilized hemoproteins, free, non-protein bound can have pro-oxidant effects. Mechanisms contributing induced generation reactive oxygen species, activation and/ or death are not fully understood. In this review, complex interactions between TLR4 critically discussed particular focus on role heme-binding serum proteins in handling extracellular its impact signaling. Finally, indirect trigger species-specific differences regulation heme-dependent signaling highlighted.

Language: Английский

Citations

50