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PubMed: 26675351

Title
Hemopexin therapy reverts heme-induced proinflammatory phenotypic switching of macrophages in a mouse model of sickle cell disease.
Journal
Blood
Volume
127
Issue
None
Pages
473-86
Date
2016-01-28
Authors
Brinkman N | Cerwenka A | Costa da Silva M | Ingoglia G | Muckenthaler MU | Petrillo S | Tolosano E | Vinchi F | Zuercher A

Evidence ad1b2997ae
JSON

Similarly, NAC prevented increased expression of MHCII, CD14, TNFα, IL-6, IL-1β, and CD86 and mildly compensated for the decrease of CD206 and IL-10 following heme treatment (Figure 4D; supplemental Figure 5).

a(CHEBI:"N-acetyl-L-cysteine") decreases complex(SCOMP:"MHC Class II Complex") View Subject | View Object

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Cell Ontology (CL)
macrophage
MeSH
Spleen
MeSH
Anemia, Sickle Cell
Text Location
Results

a(CHEBI:"N-acetyl-L-cysteine") decreases p(HGNC:CD14) View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
macrophage
MeSH
Spleen
MeSH
Anemia, Sickle Cell
Text Location
Results

a(CHEBI:"N-acetyl-L-cysteine") decreases p(HGNC:TNF) View Subject | View Object

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Cell Ontology (CL)
macrophage
MeSH
Spleen
MeSH
Anemia, Sickle Cell
Text Location
Results

a(CHEBI:"N-acetyl-L-cysteine") decreases p(HGNC:IL6) View Subject | View Object

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Annotations
Cell Ontology (CL)
macrophage
MeSH
Spleen
MeSH
Anemia, Sickle Cell
Text Location
Results

a(CHEBI:"N-acetyl-L-cysteine") decreases p(HGNC:CD86) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Spleen
MeSH
Anemia, Sickle Cell
Text Location
Results

a(CHEBI:"N-acetyl-L-cysteine") increases p(HGNC:MRC1) View Subject | View Object

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Cell Ontology (CL)
macrophage
MeSH
Spleen
MeSH
Anemia, Sickle Cell
Text Location
Results

a(CHEBI:"N-acetyl-L-cysteine") increases p(HGNC:IL10) View Subject | View Object

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Annotations
Cell Ontology (CL)
macrophage
MeSH
Spleen
MeSH
Anemia, Sickle Cell
Text Location
Results

Evidence b682f593a3
JSON

In hepatic macrophages, TAK-242 also diminished heme-driven induction of IL-6 and TNFα and NAC partially recovered CD206 downregulation ( Figure 5B-C).

a(CHEBI:"N-acetyl-L-cysteine") positiveCorrelation p(HGNC:MRC1) View Subject | View Object

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Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

a(MESH:"ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate") decreases p(HGNC:IL6) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

a(MESH:"ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate") decreases p(HGNC:TNF) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

p(HGNC:MRC1) positiveCorrelation a(CHEBI:"N-acetyl-L-cysteine") View Subject | View Object

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Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

Evidence 5d5bd8d3c2
JSON

Likewise, NAC was able to prevent iron-induced M1 polarization in M0, M1, and M2 BMDMs (supplemental Figure 13), indicating that the alteration of macrophage plasticity in response to iron is mostly explained by its pro-oxidant properties.

a(CHEBI:"N-acetyl-L-cysteine") negativeCorrelation bp(HM:"macrophage M1 polarization") View Subject | View Object

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Cell Ontology (CL)
macrophage
MeSH
Spleen
MeSH
Anemia, Sickle Cell
Text Location
Results

a(CHEBI:"iron(2+)") positiveCorrelation bp(HM:"macrophage M1 polarization") View Subject | View Object

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Cell Ontology (CL)
macrophage
MeSH
Spleen
MeSH
Anemia, Sickle Cell
Text Location
Results

bp(HM:"macrophage M1 polarization") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Spleen
MeSH
Anemia, Sickle Cell
Text Location
Results

bp(HM:"macrophage M1 polarization") negativeCorrelation a(CHEBI:"N-acetyl-L-cysteine") View Subject | View Object

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Annotations
Cell Ontology (CL)
macrophage
MeSH
Spleen
MeSH
Anemia, Sickle Cell
Text Location
Results

Evidence 64cb57d0b5
JSON

Within cells, heme is catabolized by the activity of heme oxygenases (inducible HO-1 and constitutive HO-2) into iron, carbon monoxide, and biliverdin.

a(CHEBI:"carbon monoxide") positiveCorrelation deg(a(CHEBI:heme)) View Subject | View Object

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MeSH
Anemia, Sickle Cell
Text Location
Introduction

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

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MeSH
Anemia, Sickle Cell
Text Location
Introduction

a(CHEBI:biliverdin) positiveCorrelation deg(a(CHEBI:heme)) View Subject | View Object

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MeSH
Anemia, Sickle Cell
Text Location
Introduction

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

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MeSH
Anemia, Sickle Cell
Text Location
Introduction

deg(a(CHEBI:heme)) positiveCorrelation a(CHEBI:"carbon monoxide") View Subject | View Object

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MeSH
Anemia, Sickle Cell
Text Location
Introduction

deg(a(CHEBI:heme)) positiveCorrelation a(CHEBI:biliverdin) View Subject | View Object

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MeSH
Anemia, Sickle Cell
Text Location
Introduction

Evidence 209126ae2b
JSON

Treatment with Hx or DFO diminished the increase of some M1 polarization markers in BMDMs following treatment with hemolytic RBCs (supplemental Figure 14).

a(CHEBI:"desferrioxamine B") negativeCorrelation bp(HM:"macrophage M1 polarization") View Subject | View Object

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Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

bp(HM:"macrophage M1 polarization") negativeCorrelation p(HGNC:HPX) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

bp(HM:"macrophage M1 polarization") negativeCorrelation a(CHEBI:"desferrioxamine B") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

p(HGNC:HPX) negativeCorrelation bp(HM:"macrophage M1 polarization") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

Evidence a36da6ceac
JSON

Importantly, protoporphyrin did not induce TNFα, suggesting a critical proinflammatory role for iron within the heme moiety (supplemental Figure 8).

a(CHEBI:"iron(2+)") positiveCorrelation bp(GO:"inflammatory response") View Subject | View Object

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Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

a(CHEBI:protoporphyrin) causesNoChange p(HGNC:TNF) View Subject | View Object

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Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

bp(GO:"inflammatory response") positiveCorrelation a(CHEBI:"iron(2+)") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

Evidence 57d6e4cc52
JSON

In addition, we observed increased ROS production ( Figure 2I; supplemental Figure 2), as well as an enhanced expression of IL-6 and TNFα in cells treated with heme-albumin compared with heme-Hx (Figure 2J-K).

a(CHEBI:heme) increases a(MESH:"Reactive Oxygen Species") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

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

Appears in Networks:
Annotations
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

a(CHEBI:heme) increases p(HGNC:IL6) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

Evidence a254880c36
JSON

Consistently, CD11b cells (granulocytes and monocytes) and iron-rich cells (macrophages) isolated from heme-treated Hx-null mice show a higher heme content and increased mRNA and protein expression of HO-1, Lferritin, and Fpn (Figure 1B-G) and elevated mRNA levels of the proinflammatory cytokine IL-6 ( Figure 1H).

a(CHEBI:heme) increases p(HGNC:HMOX1) View Subject | View Object

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MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

a(CHEBI:heme) increases r(HGNC:HMOX1) View Subject | View Object

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MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

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

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MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

a(CHEBI:heme) increases p(PFAM:FPN1) View Subject | View Object

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MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

a(CHEBI:heme) increases r(HGNC:IL6) View Subject | View Object

Appears in Networks:
Annotations
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

Evidence bdf21dc39f
JSON

Likewise, heme and FeNTA treatment causes the induction of the M1 markers MHCII, CD86, CD14, TNFα, IL-6, and IL1β and a decrease in the M2 markers CD206, IL-10, and Arginase-1 (the last with FeNTA only) in M0 BMDMs (Figure 3A; supplemental Figures 5, 6A, and 7).

a(CHEBI:heme) increases p(HGNC:IL1B) View Subject | View Object

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Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

a(CHEBI:heme) increases p(HGNC:IL6) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

a(CHEBI:heme) increases complex(SCOMP:"MHC Class II Complex") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

a(CHEBI:heme) increases p(HGNC:CD86) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

a(CHEBI:heme) increases p(HGNC:CD14) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

a(CHEBI:heme) decreases p(HGNC:MRC1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

a(CHEBI:heme) decreases p(HGNC:IL10) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

a(CHEBI:heme) decreases p(HGNC:ARG1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

Evidence 946914e6ed
JSON

Sickle cell disease (SCD) and malaria are paradigmatic hemolytic disorders, in which alteration in the structure of red blood cells (RBCs) leads to the release of Hb and heme into the circulation.

a(CHEBI:heme) positiveCorrelation bp(MESH:"Erythrocyte Deformability") View Subject | View Object

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MeSH
Anemia, Sickle Cell
Text Location
Introduction

bp(MESH:"Erythrocyte Deformability") positiveCorrelation p(HGNC:HBB) View Subject | View Object

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MeSH
Anemia, Sickle Cell
Text Location
Introduction

bp(MESH:"Erythrocyte Deformability") positiveCorrelation a(CHEBI:heme) View Subject | View Object

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MeSH
Anemia, Sickle Cell
Text Location
Introduction

p(HGNC:HBB) positiveCorrelation bp(MESH:"Erythrocyte Deformability") View Subject | View Object

Appears in Networks:
Annotations
MeSH
Anemia, Sickle Cell
Text Location
Introduction

Evidence 6a8ad784dd
JSON

Importantly, 15 hours after heme injection, hepatic macrophages showed iron deposition (data not shown) and an increased expression of the M1 markers MHCII and CD86 and reduced levels of the M2 markers CD206 and Arginase-1 compared with nontreated mice.

a(CHEBI:heme) increases complex(SCOMP:"MHC Class II Complex") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

a(CHEBI:heme) increases p(HGNC:CD86) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

a(CHEBI:heme) decreases p(HGNC:MRC1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

a(CHEBI:heme) decreases p(HGNC:ARG1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

Evidence 0a579bae26
JSON

Likewise, splenic macrophages from heme-treated mice show increased expression of CD86 and reduced levels of CD206 and Arginase-1 (Figure 3D).

a(CHEBI:heme) increases p(HGNC:CD86) View Subject | View Object

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Cell Ontology (CL)
macrophage
MeSH
Spleen
MeSH
Anemia, Sickle Cell
Text Location
Results

a(CHEBI:heme) decreases p(HGNC:MRC1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Spleen
MeSH
Anemia, Sickle Cell
Text Location
Results

a(CHEBI:heme) decreases p(HGNC:ARG1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Spleen
MeSH
Anemia, Sickle Cell
Text Location
Results

Evidence 8f498a3d89
JSON

This is the case in a mouse model of SCD, which is hallmarked by hemolysis, increased circulating Hb/heme, and low levels of Hp and Hx and shows elevated hepatic macrophage iron levels and M1 polarization.

a(CHEBI:heme) increases bp(HM:"macrophage M1 polarization") View Subject | View Object

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Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Discussion

p(HGNC:HBB) increases bp(HM:"macrophage M1 polarization") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Discussion

Evidence 0fb4a110b1
JSON

Importantly, by scavenging free heme, Hx prevents heme-induced M1 macrophage polarization and thus avoids both TLR4 activation and ROS formation.

a(CHEBI:heme) increases bp(HM:"macrophage M1 polarization") View Subject | View Object

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Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Discussion

a(MESH:"Reactive Oxygen Species") negativeCorrelation p(MGI:Hpx) View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Discussion

bp(HM:"macrophage M1 polarization") negativeCorrelation p(MGI:Hpx) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Discussion

p(MGI:Hpx) negativeCorrelation bp(HM:"macrophage M1 polarization") View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Discussion

p(MGI:Hpx) negativeCorrelation act(p(MGI:Tlr4)) View Subject | View Object

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Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Discussion

p(MGI:Hpx) negativeCorrelation a(MESH:"Reactive Oxygen Species") View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Discussion

act(p(MGI:Tlr4)) negativeCorrelation p(MGI:Hpx) View Subject | View Object

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Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Discussion

Evidence 1fa1853768
JSON

Our data support the idea that heme-induced phenotypic switching of macrophages toward a proinflammatory phenotype can contribute to the exacerbation of inflammation and chronic tissue injury in hemolytic disorders and that Hx therapy could alleviate these pathophysiologic consequences by preventing macrophage inflammatory activation.

a(CHEBI:heme) increases bp(HM:"macrophage M1 polarization") View Subject | View Object

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Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Discussion

bp(GO:"inflammatory response") negativeCorrelation p(MGI:Hpx) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Discussion

bp(GO:"inflammatory response") positiveCorrelation bp(HM:"macrophage M1 polarization") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Discussion

bp(GO:"inflammatory response") positiveCorrelation path(MESH:Inflammation) View Subject | View Object

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Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Discussion

bp(HM:"macrophage M1 polarization") negativeCorrelation p(MGI:Hpx) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Discussion

bp(HM:"macrophage M1 polarization") positiveCorrelation bp(GO:"inflammatory response") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Discussion

p(MGI:Hpx) negativeCorrelation bp(GO:"inflammatory response") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Discussion

p(MGI:Hpx) negativeCorrelation bp(HM:"macrophage M1 polarization") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Discussion

path(MESH:Inflammation) positiveCorrelation bp(GO:"inflammatory response") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Discussion

Evidence 02334a5244
JSON

In hepatic and splenic macrophages, cotreatment with NAC or TAK-242 reduced the heme-induced upregulation of the M1 markers MHCII and CD86 and attenuated inducible nitric oxide synthase (iNOS) expression.

a(MESH:"ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate") decreases complex(SCOMP:"MHC Class II Complex") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Spleen
MeSH
Anemia, Sickle Cell
Text Location
Results

a(MESH:"ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate") decreases p(HGNC:CD86) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Spleen
MeSH
Anemia, Sickle Cell
Text Location
Results

a(MESH:"ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate") decreases p(PFAM:"NO_synthase") View Subject | View Object

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Annotations
Cell Ontology (CL)
macrophage
MeSH
Spleen
MeSH
Anemia, Sickle Cell
Text Location
Results

Evidence a915a63353
JSON

For example, monocytes from SCD patients show an enhanced state of activation, with increased expression of interleukin (IL)-15 and production of TNFα and IL-1β.

a(MESH:Monocytes) positiveCorrelation p(HGNC:IL15) View Subject | View Object

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MeSH
Anemia, Sickle Cell
Text Location
Introduction

a(MESH:Monocytes) positiveCorrelation p(HGNC:TNF) View Subject | View Object

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MeSH
Anemia, Sickle Cell
Text Location
Introduction

a(MESH:Monocytes) positiveCorrelation p(HGNC:IL1B) View Subject | View Object

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MeSH
Anemia, Sickle Cell
Text Location
Introduction

p(HGNC:IL15) positiveCorrelation a(MESH:Monocytes) View Subject | View Object

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MeSH
Anemia, Sickle Cell
Text Location
Introduction

p(HGNC:IL1B) positiveCorrelation a(MESH:Monocytes) View Subject | View Object

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MeSH
Anemia, Sickle Cell
Text Location
Introduction

p(HGNC:TNF) positiveCorrelation a(MESH:Monocytes) View Subject | View Object

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MeSH
Anemia, Sickle Cell
Text Location
Introduction

Evidence faf21db4fa
JSON

Taken together, these data suggest that Hx administration decreases heme-driven proinflammatory activation of macrophages.

bp(GO:"inflammatory response") negativeCorrelation p(MGI:Hpx) View Subject | View Object

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Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

p(MGI:Hpx) negativeCorrelation bp(GO:"inflammatory response") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

Evidence 78bc93968b
JSON

In conclusion, an Hx-based therapy shows beneficial effects, in that it counteracts heme-induced proinflammatory activation of macrophages and attenuates some of its pathophysiologic consequences, such as chronic inflammation, hepatic fibrosis, and apoptosis (Figure 7E).

bp(GO:"inflammatory response") negativeCorrelation p(MGI:Hpx) View Subject | View Object

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Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

bp(MESH:Apoptosis) negativeCorrelation p(MGI:Hpx) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

p(MGI:Hpx) negativeCorrelation bp(GO:"inflammatory response") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

p(MGI:Hpx) negativeCorrelation path(MESH:Inflammation) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

p(MGI:Hpx) negativeCorrelation path(MESH:Fibrosis) View Subject | View Object

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Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

p(MGI:Hpx) negativeCorrelation bp(MESH:Apoptosis) View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

path(MESH:Fibrosis) negativeCorrelation p(MGI:Hpx) View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

path(MESH:Inflammation) negativeCorrelation p(MGI:Hpx) View Subject | View Object

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Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

Evidence 019aaf30c8
JSON

Cotreatment of M0 BMDMs with heme and TAK-242 attenuated the increase of the M1 markers MHCII, CD14, TNFα, IL-6, IL-1β, and CD86 and the decrease of the M2 marker CD206, IL-10, and Ym1 in comparison with heme treatment alone ( Figure 4A; supplemental Figures 5 and 12).

complex(a(CHEBI:heme), a(MESH:"ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate")) decreases complex(SCOMP:"MHC Class II Complex") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Spleen
MeSH
Anemia, Sickle Cell
Text Location
Results

complex(a(CHEBI:heme), a(MESH:"ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate")) decreases p(HGNC:CD14) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Spleen
MeSH
Anemia, Sickle Cell
Text Location
Results

complex(a(CHEBI:heme), a(MESH:"ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate")) decreases p(HGNC:TNF) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Spleen
MeSH
Anemia, Sickle Cell
Text Location
Results

complex(a(CHEBI:heme), a(MESH:"ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate")) decreases p(HGNC:IL6) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Spleen
MeSH
Anemia, Sickle Cell
Text Location
Results

complex(a(CHEBI:heme), a(MESH:"ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate")) decreases p(HGNC:IL1B) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Spleen
MeSH
Anemia, Sickle Cell
Text Location
Results

complex(a(CHEBI:heme), a(MESH:"ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate")) decreases p(HGNC:CD86) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Spleen
MeSH
Anemia, Sickle Cell
Text Location
Results

complex(a(CHEBI:heme), a(MESH:"ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate")) increases p(HGNC:MRC1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Spleen
MeSH
Anemia, Sickle Cell
Text Location
Results

complex(a(CHEBI:heme), a(MESH:"ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate")) increases p(HGNC:IL10) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Spleen
MeSH
Anemia, Sickle Cell
Text Location
Results

Evidence 162d186845
JSON

Recently, we demonstrated that Hx controls hepatic heme uptake and thus limits heme accumulation in extrahepatic tissues, such as the vessel wall and the heart, preventing heme-induced toxicity and tissue injury.

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

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MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

Evidence 7f493a8e6f
JSON

Taken together, these data demonstrate that Hx limits macrophage heme overload and prevents the prooxidant and proinflammatory effects triggered by heme in cellular assays and in vivo.

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

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Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

p(HGNC:HPX) decreases a(MESH:"Reactive Oxygen Species") View Subject | View Object

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Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

p(HGNC:HPX) decreases bp(GO:"inflammatory response") View Subject | View Object

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Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

Evidence 54dc1107fa
JSON

In addition, Hx and DFO prevented the heme- and ironmediated induction of the M1 markers MHCII, CD86, CD14, and TNFα and the decrease of some M2 markers, such as CD206, IL-10, and Arginase-1 (the last for FeNTA only) in M0 BMDMs (Figure 6A; supplemental Figure 15A).

p(HGNC:HPX) decreases complex(SCOMP:"MHC Class II Complex") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

p(HGNC:HPX) decreases p(HGNC:CD86) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

p(HGNC:HPX) decreases p(HGNC:CD14) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

p(HGNC:HPX) decreases p(HGNC:TNF) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

p(HGNC:HPX) positiveCorrelation p(HGNC:MRC1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

p(HGNC:HPX) positiveCorrelation p(HGNC:ARG1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

p(HGNC:HPX) positiveCorrelation p(HGNC:IL10) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

p(HGNC:ARG1) positiveCorrelation p(HGNC:HPX) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

p(HGNC:IL10) positiveCorrelation p(HGNC:HPX) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

p(HGNC:MRC1) positiveCorrelation p(HGNC:HPX) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

Evidence f31b5b7d8d
JSON

We therefore next analyzed heme-Hx-treated wild-type mice that showed decreased hepatic expression of collagens, TGFβ, PDGF, SMA, and the tissue inhibitor of MMPs, TIMP2, as well as increased expression of the M2 polarizing colony stimulating factor-1 and MMPs compared with heme-HSA–treated mice ( Figure 7C).

complex(a(CHEBI:heme), p(MGI:Hpx)) decreases p(MGI:Tgfb1) View Subject | View Object

Appears in Networks:
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Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

complex(a(CHEBI:heme), p(MGI:Hpx)) decreases p(PFAM:PDGF) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

complex(a(CHEBI:heme), p(MGI:Hpx)) decreases p(MGI:Acta2) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

complex(a(CHEBI:heme), p(MGI:Hpx)) decreases p(MGI:Timp2) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

complex(a(CHEBI:heme), p(MGI:Hpx)) increases p(MGI:Csf1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

complex(a(CHEBI:heme), p(MGI:Hpx)) increases p(INTERPRO:"Peptidase M10A") View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

Evidence 07d19ef263
JSON

Here we show that Hx treatment decreases expression of the M1 cytokine TNFα, the monocyte chemoattractant protein (MCP)1, and the profibrotic and mitogenic cytokines transforming growth factor (TGF)β and platelet-derived growth factor (PDGF) in the liver of sickle mice.

p(MGI:Hpx) decreases p(MGI:Tnf) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

p(MGI:Hpx) decreases p(MGI:Ccl2) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

p(MGI:Hpx) decreases p(MGI:Tgfb1) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

p(MGI:Hpx) decreases p(PFAM:PDGF) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

Evidence 136cef406e
JSON

Moreover, Hx administration increases hepatic expression of the matrix metalloproteinases MMP-9, MMP-12, and MMP-13 (mostly expressed by M2 macrophages).

p(MGI:Hpx) increases p(MGI:Mmp9) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

p(MGI:Hpx) increases p(MGI:Mmp12) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

p(MGI:Hpx) increases p(MGI:Mmp13) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

Evidence 784e5adacd
JSON

It further increases the expression of a marker for resting HSCs, synaptophysin, and reduces the expression of a marker for activated myofibroblast-like HSCs, smooth muscle actin (SMA) (Figure 7B).

p(MGI:Hpx) decreases p(MGI:Acta2) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
Text Location
Results

p(MGI:Hpx) increases p(MGI:Syp) View Subject | View Object

Appears in Networks:
Annotations
Cell Ontology (CL)
macrophage
MeSH
Liver
MeSH
Anemia, Sickle Cell
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.