Hemolysis, free hemoglobin toxicity, and scavenger protein therapeutics

Vallelian, Florence; Buehler, Paul W.; Schaer, Dominik J.

doi:10.1182/blood.2022015596

Cited by 51 publications

(43 citation statements)

References 102 publications

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“…Currently, we can speculate that the tissue damage caused by the acute bleeding releases multiple tissue damage-associated molecular patterns (DAMPs) into the interstitial space of the brain. Additionally, the lysis of red blood cells may liberate large quantities of cell-free hemoglobin, which is prone to auto-oxidation and release of the TLR4 agonist heme 14,[29][30][31] . We detected high levels of hemoglobin subunit transcripts in the CP as early as 2h after the striatal injection of whole-blood.…”

Section: Discussionmentioning

confidence: 99%

MyD88-TLR4-dependent choroid plexus activation precedes perilesional inflammation and edema in intracerebral hemorrhage

Akeret

Buzzi

Thomson

et al. 2022

Preprint

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The functional neurological outcome of patients with intracerebral hemorrhage (ICH) strongly relates to the degree of secondary brain injury (ICH SBI) evolving within days after the initial bleeding. Different mechanisms including the incitement of inflammatory pathways, dysfunction of the blood brain barrier (BBB), activation of resident microglia, and an influx of blood-borne immune cells, have been hypothesized to contribute to ICH SBI. Yet, the spatiotemporal interplay of specific inflammatory processes within different brain compartments has not been sufficiently characterized, limiting potential therapeutic interventions to prevent and treat ICH SBI. Using a whole-blood injection model in mice, we systematically characterized the spatial and temporal dynamics of inflammatory processes after ICH using 7 Tesla magnetic resonance imaging (MRI), spatial RNA sequencing (spRNAseq), functional BBB assessment, and immunofluorescence average intensity mapping. We identified a pronounced early response of the choroid plexus (CP) peaking at 12 to 24h, that was characterized by inflammatory cytokine expression, epithelial and endothelial expression of leukocyte adhesion molecules, and the accumulation of leukocytes. In contrast, we observed a delayed secondary reaction pattern at the injection site (striatum) peaking at 96h, defined by gene expression corresponding to perilesional leukocyte infiltration and correlating to the delayed signal alteration seen on MRI. Pathway analysis revealed a dependence of the early inflammatory reaction in the CP on toll-like receptor 4 (TLR4) signaling via myeloid differentiation factor 88 (MyD88). TLR4 and MyD88 knockout mice corroborated this observation, lacking the early upregulation of adhesion molecules and leukocyte infiltration within the CP 24h after whole-blood injection. In conclusion, we report a biphasic brain reaction pattern after ICH with a MyD88 TLR4 dependent early inflammatory response of the CP, preceding inflammation, edema and leukocyte infiltration at the lesion site. Pharmacological targeting of the early CP activation might harbor the potential to modulate the development of ICH SBI.

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Section: Discussionmentioning

confidence: 99%

MyD88-TLR4-dependent choroid plexus activation precedes perilesional inflammation and edema in intracerebral hemorrhage

Akeret

Buzzi

Thomson

et al. 2022

Preprint

Self Cite

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“…While the binding of haptoglobin to intact Hb dimers is well characterized and its protection against Hb toxicity has been revealed [ 71 ], the binding of ferryl-Hb to haptoglobin hasn't been studied in details. Haptoglobin binding of Hb decreases both the ferryl iron and free radical reactivity of Hb during peroxide challenge [ 69 ].…”

Section: Proposed Protective Pathways Of H 2 S On ...mentioning

confidence: 99%

Overview on hydrogen sulfide-mediated suppression of vascular calcification and hemoglobin/heme-mediated vascular damage in atherosclerosis

Gáll¹,

Garai²,

Potor³

et al. 2022

Redox Biology

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“…Hb can cause oxidation of proteins, lipids, and nucleic acids 2 , 51 , 52 . Therefore, this protein should be rapidly removed from the circulation 6 , 53 , 54 . The principle Hb scavenger in the plasma is haptoglobin 6 , 55 , 56 .…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, this protein should be rapidly removed from the circulation 6 , 53 , 54 . The principle Hb scavenger in the plasma is haptoglobin 6 , 55 , 56 . This protein tightly binds Hb and delivers it (through interaction with CD163) to macrophages for degradation 57 .…”

Section: Introductionmentioning

confidence: 99%

Oxidized hemoglobin triggers polyreactivity and autoreactivity of human IgG via transfer of heme

et al. 2023

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Intravascular hemolysis occurs in diverse pathological conditions. Extracellular hemoglobin and heme have strong pro-oxidative and pro-inflammatory potentials that can contribute to the pathology of hemolytic diseases. However, many of the effects of extracellular hemoglobin and heme in hemolytic diseases are still not well understood. Here we demonstrate that oxidized hemoglobin (methemoglobin) can modify the antigen-binding characteristics of human immunoglobulins. Thus, incubation of polyclonal or some monoclonal human IgG in the presence of methemoglobin results in an appearance of binding reactivities towards distinct unrelated self-proteins, including the protein constituent of hemoglobin i.e., globin. We demonstrate that a transfer of heme from methemoglobin to IgG is indispensable for this acquisition of antibody polyreactivity. Our data also show that only oxidized form of hemoglobin have the capacity to induce polyreactivity of antibodies. Site-directed mutagenesis of a heme-sensitive human monoclonal IgG1 reveals details about the mechanism of methemoglobin-induced antigen-binding polyreactivity. Further here we assess the kinetics and thermodynamics of interaction of a heme-induced polyreactive human antibody with hemoglobin and myoglobin. Taken together presented data contribute to a better understanding of the functions of extracellular hemoglobin in the context of hemolytic diseases.

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Hemolysis, free hemoglobin toxicity, and scavenger protein therapeutics

Cited by 51 publications

References 102 publications

MyD88-TLR4-dependent choroid plexus activation precedes perilesional inflammation and edema in intracerebral hemorrhage

MyD88-TLR4-dependent choroid plexus activation precedes perilesional inflammation and edema in intracerebral hemorrhage

Overview on hydrogen sulfide-mediated suppression of vascular calcification and hemoglobin/heme-mediated vascular damage in atherosclerosis

Oxidized hemoglobin triggers polyreactivity and autoreactivity of human IgG via transfer of heme

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