1. Catalog
  2. Citations
  3. PubMed:29610666

PubMed: 29610666

Title
Revisiting the putative role of heme as a trigger of inflammation.
Journal
Pharmacology research & perspectives
Volume
6
Issue
None
Pages
e00392
Date
2018-04-01
Authors
Buehler PW | Deuel JW | Humar R | Ingoglia G | Schaer CA | Schaer DJ | Vallelian F

Evidence 54d9ce3daa
JSON

In contrast, less ATP depletion was observed during exposure to heme-albumin, and no effect could be detected when either cell type was exposed to metHb or oxyHb at concentrations of up to 500 lmolL1, even in the absence of serum.

a(CHEBI:"adenosine triphosphate") positiveCorrelation complex(a(CHEBI:heme), p(HGNC:ALB)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
neutrophil
MeSH
Human Umbilical Vein Endothelial Cells
Text Location
Results

a(CHEBI:methemoglobin) causesNoChange a(CHEBI:"adenosine triphosphate") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
neutrophil
MeSH
Human Umbilical Vein Endothelial Cells
Text Location
Results

a(CHEBI:oxyhemoglobin) causesNoChange a(CHEBI:"adenosine triphosphate") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
neutrophil
MeSH
Human Umbilical Vein Endothelial Cells
Text Location
Results

complex(a(CHEBI:heme), p(HGNC:ALB)) positiveCorrelation a(CHEBI:"adenosine triphosphate") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
neutrophil
MeSH
Human Umbilical Vein Endothelial Cells
Text Location
Results

Evidence c612257130
JSON

These experiments confirm a number of earlier reports and support the idea that certain solutions derived from purified/crystalline heme have the potential to induce weak TLR4-mediated inflammatory responses in macrophages in the complete absence of plasma derived proteins.

a(CHEBI:heme) increases bp(GO:"inflammatory response") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Mitochondria
Text Location
Results

Evidence 0913e22696
JSON

By modeling the equilibrium concentration in the experiments performed with heme-albumin we could show that the free heme is the active neutrophil-stimulating component, which is inactivated by protein association (Figure S2).

a(CHEBI:heme) positiveCorrelation bp(GO:"neutrophil activation") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
neutrophil
Text Location
Results

bp(GO:"neutrophil activation") positiveCorrelation a(CHEBI:heme) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
neutrophil
Text Location
Results

Evidence 8989775f27
JSON

Purified heme was found to be an activator of TLR4 8,11,27 in some studies and of the inflammasome 9 in others, and these activities were considered to be the molecular mechanism behind the coexistence of inflammation and hemolysis.

a(CHEBI:heme) increases act(p(HGNC:TLR4)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Mitochondria
Text Location
Discussion

Evidence efa24479fd
JSON

Only under protein-free conditions did we observe a limited heme-induced TNF-alpha response in cultured macrophages, which was triggered via signaling of the classical TLR4–MyD88–TRIF pathway of NF-kB activation.28

a(CHEBI:heme) increases p(HGNC:TLR4) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Mitochondria
Text Location
Discussion

p(HGNC:TLR4) increases p(HGNC:MYD88) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Mitochondria
Text Location
Discussion

p(HGNC:TLR4) increases p(HGNC:TICAM1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Mitochondria
Text Location
Discussion

p(HGNC:MYD88) increases act(p(HGNC:NFKB1)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Mitochondria
Text Location
Discussion

act(p(HGNC:NFKB1)) increases p(HGNC:TNF) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Mitochondria
Text Location
Discussion

p(HGNC:TICAM1) increases act(p(HGNC:NFKB1)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Mitochondria
Text Location
Discussion

Evidence 56760b3f2c
JSON

In subsequent reactions, metHb or metHb-derived heme participates in redox chain reactions that lead to the accumulation of modified lipids and proteins, as well as to heme degradation and to the release of free iron.19,25

deg(a(CHEBI:heme)) increases a(CHEBI:"iron(2+)") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Mitochondria
Text Location
Discussion

a(CHEBI:methemoglobin) increases deg(a(CHEBI:heme)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Mitochondria
Text Location
Discussion

Evidence 32b3dd3676
JSON

Exposure of washed human peripheral blood leukocytes to protein free crystalline heme that has been dissolved in NaOH (100 mmolL1) with subsequent adjustment to pH 7.8 resulted in a drastic reduction in cell surface CD62L expression on CD14 low CD15 high neutrophil granulocytes after 30 minutes of exposure (Figure 1A).

a(CHEBI:heme) decreases p(HGNC:SELL) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
neutrophil
Text Location
Results

Evidence 82c3ebc977
JSON

These observations suggest that in any physiological scenario in which heme might be present in extracellular spaces as a component of a natural hemoprotein, the concentration of free or quasi-free heme can be expected to be very low, possibly below the minimum range required to trigger granulocyte activation and other innate immunity responses.

a(CHEBI:heme) positiveCorrelation bp(GO:"granulocyte activation") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
neutrophil
Text Location
Results

bp(GO:"granulocyte activation") positiveCorrelation a(CHEBI:heme) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
neutrophil
Text Location
Results

Evidence e09db71312
JSON

In serum-free conditions, NaOH-dissolved heme (final pH 7.8) reduced cellular ATP in both cell types in a dose-dependent manner after 8 hours of exposure (Figure 2A)

a(CHEBI:heme) decreases a(CHEBI:"adenosine triphosphate") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
neutrophil
MeSH
Human Umbilical Vein Endothelial Cells
Text Location
Results

Evidence f4438b8eff
JSON

This experiment demonstrated that under serum-free conditions, 4 hours of exposure to NaOH-dissolved heme induced complete deterioration of mitochondrial respiration at concentrations as low as 10 lmolL1, while exposure to albumin-associated heme in the presence of 2% FCS stimulated respiratory capacity to levels above baseline.

a(CHEBI:heme) decreases bp(GO:"cellular respiration") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
neutrophil
MeSH
Mitochondria
Text Location
Results

bp(GO:"cellular respiration") positiveCorrelation complex(a(CHEBI:heme), p(HGNC:ALB)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
neutrophil
MeSH
Mitochondria
Text Location
Results

complex(a(CHEBI:heme), p(HGNC:ALB)) positiveCorrelation bp(GO:"cellular respiration") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
neutrophil
MeSH
Mitochondria
Text Location
Results

Evidence 2ed095f2c7
JSON

However, a weak TNF-alpha signal appeared in macrophages that were treated with the highest concentration of NaOH-dissolved heme (500 lmolL1).

a(CHEBI:heme) positiveCorrelation p(MGI:Tnf) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Mitochondria
Text Location
Results

p(MGI:Tnf) positiveCorrelation a(CHEBI:heme) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Mitochondria
Text Location
Results

Evidence 74d8d73315
JSON

The second biochemical process relates to the ability of Hb to facilitate oxidative reactions outside of the reducing environment of the RBC, leading to the accumulation of ferric metHb(Fe3+) in tissue.24

a(HM:"oxidative reactions") positiveCorrelation p(HGNC:HBB) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Mitochondria
Text Location
Discussion

p(HGNC:HBB) positiveCorrelation a(HM:"oxidative reactions") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Mitochondria
Text Location
Discussion

p(HGNC:HBB) increases a(CHEBI:methemoglobin) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Mitochondria
Text Location
Discussion

Evidence 77a4771717
JSON

However, similar to Hb, heme-albumin did not induce an inflammatory response in macrophages or endothelial cells in the presence of low concentrations of serum.

bp(GO:"inflammatory response") negativeCorrelation complex(a(CHEBI:heme), p(HGNC:ALB)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Mitochondria
Text Location
Discussion

complex(a(CHEBI:heme), p(HGNC:ALB)) negativeCorrelation bp(GO:"inflammatory response") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Mitochondria
Text Location
Discussion

Evidence cd72235a48
JSON

The first process links the nitric oxide (NO) reactivity of oxyHb to a cascade of cell-free Hb extravasation, hemolysis-associated NO-depletion, and vasoconstriction.21–23

bp(MESH:Vasoconstriction) positiveCorrelation p(HGNC:HBB) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Mitochondria
Text Location
Discussion

p(HGNC:HBB) decreases a(CHEBI:"nitric oxide") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Mitochondria
Text Location
Discussion

p(HGNC:HBB) positiveCorrelation bp(MESH:Vasoconstriction) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Mitochondria
Text Location
Discussion

Evidence 25a50e6e39
JSON

In endothelial cells, we found that, in the absence of serum, heme-albumin triggered a dose-dependent HMOX1 protein expression signal in an exposure range of 0–175 lmolL1.

complex(a(CHEBI:heme), p(HGNC:ALB)) positiveCorrelation p(HGNC:HMOX1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Mitochondria
Text Location
Results

p(HGNC:HMOX1) positiveCorrelation complex(a(CHEBI:heme), p(HGNC:ALB)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Mitochondria
Text Location
Results

Evidence 53c218261f
JSON

heme-albumin is also a robust inducer of dose-dependent HMOX1 expression in BMDMs (Figure 2D).

complex(a(CHEBI:heme), p(HGNC:ALB)) positiveCorrelation p(HGNC:HMOX1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Mitochondria
Text Location
Results

p(HGNC:HMOX1) positiveCorrelation complex(a(CHEBI:heme), p(HGNC:ALB)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Mitochondria
Text Location
Results

Evidence faf289ac87
JSON

heme-albumin, in contrast, induced HMOX1 in a dose-dependent manner.

complex(a(CHEBI:heme), p(HGNC:ALB)) positiveCorrelation p(HGNC:HMOX1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Mitochondria
Text Location
Results

p(HGNC:HMOX1) positiveCorrelation complex(a(CHEBI:heme), p(HGNC:ALB)) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
endothelial cell
MeSH
Mitochondria
Text Location
Results

About

BEL Commons is developed and maintained in an academic capacity by Charles Tapley Hoyt and Daniel Domingo-Fernández at the Fraunhofer SCAI Department of Bioinformatics with support from the IMI project, AETIONOMY. It is built on top of PyBEL, an open source project. Please feel free to contact us here to give us feedback or report any issues. Also, see our Publishing Notes and Data Protection information.

If you find BEL Commons useful in your work, please consider citing: Hoyt, C. T., Domingo-Fernández, D., & Hofmann-Apitius, M. (2018). BEL Commons: an environment for exploration and analysis of networks encoded in Biological Expression Language. Database, 2018(3), 1–11.