Oxidized hemoglobin forms contribute to NLRP3 inflammasome-driven IL-1β production upon intravascular hemolysis

Nyakundi, Benard Bogonko; Tóth, Andrea; Balogh, Enikő; Nagy, Béla; Erdei, J.; Ryffel, Bernhard; Paragh, György; Cordero, Mario D.; Jeney, Viktória

doi:10.1016/j.bbadis.2018.10.030

Cited by 39 publications

(42 citation statements)

References 72 publications

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“…Besides CSF analysis, we used a well-established model of acute sterile hemolysis to investigate the formation of the different Hb species in vivo. In agreement with previous observations [27,50,51], we found that the injection of PHZ triggered a marked elevation of extracellular heme content in the plasma. The determination of the distribution of the extracellular heme among the different redox states of Hb revealed that Hb dominates at an early time point (4 h), and hemichrome becomes more dominant at later time points.…”

supporting

confidence: 93%

“…In contrast, the concentration of acellular Hb and oxidized Hb forms can be particularly high (up to several hundred μmol heme/L) following hemolysis, still the contribution of these Hb forms to the pathogenesis of hemolytic conditions remained rather elusive [27]. The biological effect of Hb depends on the precise nature of heme/iron redox states; therefore, accurate quantification of oxidized Hb forms is particularly important.…”

Section: Introductionmentioning

confidence: 99%

“…The exposure of endothelial cells to gmoxHb induces the upregulation of adhesion molecules such as vascular cell adhesion molecule-1, intercellular adhesion molecule-1, and E-selectin and induces intercellular gap formation that is dependent on actin polymerization and the activation of the c-Jun N-terminal kinase and the p38 mitogen-activated protein kinase signal transduction pathways [3,30]. Moreover, gmoxHb serves as a damageassociated molecular pattern (DAMP) inducing the Nucleotide-binding domain, Leucine-rich Repeat containing Protein 3 (NLRP3) inflammasome activation, and subsequent production of interleukin 1 beta in macrophages [27].…”

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confidence: 99%

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Formation and Detection of Highly Oxidized Hemoglobin Forms in Biological Fluids during Hemolytic Conditions

Nyakundi

Erdei

Tóth

et al. 2020

Oxidative Medicine and Cellular Longevity

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Hemolytic diseases are characterized by an accelerated breakdown of red blood cells (RBCs) and the release of hemoglobin (Hb). Following, RBC lysis Hb oxidation occurs with the formation of different redox states of Hb (metHb and ferrylHb) and the release of heme. ferrylHb is unstable and decomposes to metHb with the concomitant formation of globin radicals and eventually covalently crosslinked Hb multimers. The goal of the present study was to determine the concentrations of the different redox states of Hb in biological samples during hemolytic conditions. We used plasma and urine samples of mice with intravascular hemolysis and human cerebrospinal fluid (CSF) samples following intraventricular hemorrhage. Because ferrylHb is highly unstable, we also addressed the fate of this species. metHb and free heme time-dependently accumulate in plasma and CSF samples following intravascular hemolysis and intraventricular hemorrhage, respectively. ferrylHb is hardly detectable in the biological samples during hemolytic conditions. Under in vitro conditions, ferrylHb decomposes quickly to metHb, which process is associated with the formation of covalently crosslinked Hb multimers. We detected these covalently crosslinked Hb multimers in plasma, urine, and CSF samples during hemolytic conditions. Because globin modification is specific for these Hb forms, we propose to call this heterogeneous form of Hb produced during ferrylHb decomposition as globin-modified oxidized Hb (gmoxHb). Understanding the formation and the contribution of gmoxHb species to the pathogenesis of hemolytic conditions could have therapeutic implications in the treatment of hemolytic diseases.

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confidence: 93%

Section: Introductionmentioning

confidence: 99%

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confidence: 99%

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Formation and Detection of Highly Oxidized Hemoglobin Forms in Biological Fluids during Hemolytic Conditions

Nyakundi

Erdei

Tóth

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…We prepared Hb, metHb, and ferrylHb from fresh blood obtained from healthy volunteers as described in detail in our previous work (12). Briefly, Hb was isolated from fresh blood drawn from healthy volunteers using ion-exchange chromatography on a DEAE Sepharose CL-6B column.…”

Section: Hemoglobin Preparationmentioning

confidence: 99%

“…Then the termination of the reaction occurs when these globin radicals react with each other leading to the formation of covalently cross-linked Hb multimers [reviewed in Jeney et al (9)]. Covalently cross-linked oxidized Hb forms have been detected in different biological samples including plasma following intravascular hemolysis as well as in human complicated atherosclerotic lesions with intraplaque hemorrhage (11,12).…”

Section: Introductionmentioning

confidence: 99%

The Role of Hemoglobin Oxidation Products in Triggering Inflammatory Response Upon Intraventricular Hemorrhage in Premature Infants

et al. 2020

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Intraventricular hemorrhage (IVH) is a frequent complication of prematurity that is associated with high neonatal mortality and morbidity. IVH is accompanied by red blood cell (RBC) lysis, hemoglobin (Hb) oxidation, and sterile inflammation. Here we investigated whether extracellular Hb, metHb, ferrylHb, and heme contribute to the inflammatory response after IVH. We collected cerebrospinal fluid (CSF) (n = 20) from premature infants with grade III IVH at different time points after the onset of IVH. Levels of Hb, metHb, total heme, and free heme were the highest in CSF samples obtained between days 0 and 20 after the onset of IVH and were mostly non-detectable in CSF collected between days 41 and 60 of post-IVH. Besides Hb monomers, we detected cross-linked Hb dimers and tetramers in post-IVH CSF samples obtained in days 0-20 and 21-40, but only Hb tetramers were present in CSF samples obtained after 41-60 days. Vascular cell adhesion molecule-1 (VCAM-1) and interleukin-8 (IL-8) levels were higher in CSF samples obtained between days 0 and 20 than in CSF collected between days 41 and 60 of post-IVH. Concentrations of VCAM-1, intercellular adhesion molecule-1 (ICAM-1), and IL-8 strongly correlated with total heme levels in CSF. Applying the identified heme sources on human brain microvascular endothelial cells revealed that Hb oxidation products and free heme contribute to the inflammatory response. We concluded that RBC lysis, Hb oxidation, and heme release are important components of the inflammatory response in IVH. Pharmacological interventions targeting cellfree Hb, Hb oxidation products, and free heme could have potential to limit the neuroinflammatory response following IVH.

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NLRP3 Inflammasome Overactivation in Patients with Aneurysmal Subarachnoid Hemorrhage

Nanwani-Nanwani

García-Tovar²,

Alfaro³

et al. 2022

Transl. Stroke Res.

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Aneurysmal subarachnoid hemorrhage (aSAH) is an uncommon and severe subtype of stroke leading to the loss of many years of productive life. We analyzed NLRP3 activity as well as key components of the inflammasome cascade in monocytes and plasma from 28 patients with aSAH and 14 normal controls using flow cytometry, western blot, ELISA, and qPCR technologies. Our data reveal that monocytes from patients with aSAH present an overactivation of the NLRP3 inflammasome, which results in the presence of high plasma levels of interleukin (IL)-1β, IL-18, gasdermin D, and tissue factor. Although further research is needed, we propose that serum tissue factor concentration might be a useful prognosis biomarker for clinical outcome, and for Tako-Tsubo cardiomyopathy and cerebral vasospasm prediction. Remarkably, MCC-950 inhibitor effectively blocks NLRP3 activation in aSAH monocyte culture and supresses tissue factor release to the extracellular space. Finally, our findings suggest that NLRP3 activation could be due to the release of erythrocyte breakdown products to the subarachnoid space during aSAH event. These data define NLRP3 activation in monocytes from aSAH patients, indicating systemic inflammation that results in serum TF upregulation which in turns correlates with aSAH severity and might serve as a prognosis biomarker for aSAH clinical outcome and for cerebral vasospasm and Tako-Tsubo cardiomyopathy prediction.

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Oxidized hemoglobin forms contribute to NLRP3 inflammasome-driven IL-1β production upon intravascular hemolysis

Cited by 39 publications

References 72 publications

Formation and Detection of Highly Oxidized Hemoglobin Forms in Biological Fluids during Hemolytic Conditions

Formation and Detection of Highly Oxidized Hemoglobin Forms in Biological Fluids during Hemolytic Conditions

The Role of Hemoglobin Oxidation Products in Triggering Inflammatory Response Upon Intraventricular Hemorrhage in Premature Infants

NLRP3 Inflammasome Overactivation in Patients with Aneurysmal Subarachnoid Hemorrhage

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