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PubMed: 27798618

Title
Heme drives hemolysis-induced susceptibility to infection via disruption of phagocyte functions.
Journal
Nature immunology
Volume
17
Issue
None
Pages
1361-1372
Date
2016-12-01
Authors
Martins R | Knapp S | Aichinger MC | Bennett KL | Brown M | Colinge J | Decker T | Duggan M | Eisenbarth SC | Esterbauer H | Gawish R | Gorki AD | Hladik A | Huber KV | Kerjaschki D | Korosec A | Kubicek S | Lakovits K | Lardeau CH | Maier J | Quattrone F | Radic-Sarikas B | Saluzzo S | Sharif O | Sixt M | Starkl P | Superti-Furga G | Vaahtomeri K

Evidence f34581484f
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Chelation of growth-medium iron with deferoxamine (DFO, 10 μM) led to a reduction in bacterial growth, as compared with non-chelated controls (Fig. 2a).

a(CHEBI:"desferrioxamine B") decreases bp(MESH:"Bacterial Load") View Subject | View Object

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Cell Ontology (CL)
macrophage
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Plasma
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Evidence 18c49f8981
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Heme is an amphipathic molecule that can promote the generation of reactive oxygen species (ROS) via Fenton chemistry, thereby leading to membrane damage.

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

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monocyte
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Blood
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a(MESH:"Reactive Oxygen Species") positiveCorrelation a(CHEBI:heme) View Subject | View Object

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Evidence b86128e00a
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Following i.p. E. coli infection, we observed a significant increase in plasma heme levels in LysM-Cre+/−Hmox1fl/fl mice (Fig. 1e and Supplementary Fig. 1c), which was accompanied by increased bacterial numbers in blood and liver (Fig. 1f and Supplementary Fig. 1d) and impaired survival (Fig. 1g) when compared with LysM-Cre−/−Hmox1fl/fl controls.

a(CHEBI:heme) positiveCorrelation bp(MESH:"Bacterial Load") View Subject | View Object

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Cell Ontology (CL)
macrophage
MeSH
Plasma
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bp(MESH:"Bacterial Load") positiveCorrelation a(CHEBI:heme) View Subject | View Object

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macrophage
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Evidence 439c2bec53
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Thus, enhanced levels of plasma heme, induced by either exogenous heme administration or a lack of HO-1 expression in macrophages, resulted in an increased susceptibility to E. coli sepsis.

a(CHEBI:heme) positiveCorrelation bp(MESH:"Bacterial Load") View Subject | View Object

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Cell Ontology (CL)
macrophage
MeSH
Plasma
MeSH
Sepsis
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bp(MESH:"Bacterial Load") positiveCorrelation a(CHEBI:heme) View Subject | View Object

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Cell Ontology (CL)
macrophage
MeSH
Plasma
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Evidence dbac98f042
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Plasma heme amounts were comparable in mice pretreated with Fe3+ or PBS (Fig. 2d), and despite the similarly increased availability of iron in both heme- and Fe3+-treated mice (Fig. 2e), only heme-treated mice presented a significantly higher bacterial burden in the blood and liver compared with PBS- or Fe3+-treated mice (Fig. 2f).

a(CHEBI:heme) positiveCorrelation bp(MESH:"Bacterial Load") View Subject | View Object

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Cell Ontology (CL)
macrophage
MeSH
Blood
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bp(MESH:"Bacterial Load") positiveCorrelation a(CHEBI:heme) View Subject | View Object

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macrophage
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Blood
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Evidence ec2983743a
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These results indicate that increased heme concentrations directly lead to increased bacterial counts during sepsis and that bacterial iron requirements are met via heme-independent mechanisms.

a(CHEBI:heme) positiveCorrelation bp(MESH:"Bacterial Load") View Subject | View Object

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Blood
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bp(MESH:"Bacterial Load") positiveCorrelation a(CHEBI:heme) View Subject | View Object

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macrophage
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Evidence 77dde8031b
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We focused on macrophage effector functions and found that heme pretreatment (15 min, 3–30 μM unless otherwise indicated) led to a strong, dose-dependent reduction of phagocytosis of E. coli by RAW264.7 macrophages compared with DMSO-treated controls (Fig. 3a,b and Supplementary Fig. 2a).

a(CHEBI:heme) negativeCorrelation bp(MESH:Phagocytosis) View Subject | View Object

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macrophage
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Blood
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bp(MESH:Phagocytosis) negativeCorrelation a(CHEBI:heme) View Subject | View Object

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macrophage
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Evidence e03622b571
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Induction of hemolysis with phenylhydrazine or addition of heme to whole blood at concentrations mimicking the physiological range of plasma heme in hemolytic patients (5–50 μM)6 led to a dose-dependent impairment of E. coli phagocytosis by neutrophils and monocytes, as compared with DMSO controls (Fig. 3g and Supplementary Fig. 2n,o), indicating that our mouse model was reflective of human hemolytic conditions.

a(CHEBI:heme) negativeCorrelation bp(MESH:Phagocytosis) View Subject | View Object

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Blood
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bp(MESH:Phagocytosis) negativeCorrelation a(CHEBI:heme) View Subject | View Object

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Evidence d69bfe55e7
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In addition, we observed that heme treatment of RAW264.7 macrophages led to a dose-dependent inhibition of apoptotic cell uptake (Supplementary Fig. 2m).

a(CHEBI:heme) negativeCorrelation bp(GO:"engulfment of apoptotic cell") View Subject | View Object

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Cell Ontology (CL)
macrophage
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Blood
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bp(GO:"engulfment of apoptotic cell") negativeCorrelation a(CHEBI:heme) View Subject | View Object

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Cell Ontology (CL)
macrophage
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Blood
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Evidence f6fff4c63f
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We quantified these changes by automatic image analysis and found that heme-induced cytoskeleton rearrangement led to a significant increase in cell area and perimeter, as well as a decrease in circularity (form factor) (Fig. 4d,e and Supplementary Fig. 3b–d), indicating that the heme-induced defective phagocytic response was likely tied to cytoskeleton rearrangements.

a(CHEBI:heme) positiveCorrelation bp(GO:"actin cytoskeleton reorganization") View Subject | View Object

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Cell Ontology (CL)
monocyte
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Blood
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bp(GO:"actin cytoskeleton reorganization") positiveCorrelation a(CHEBI:heme) View Subject | View Object

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Cell Ontology (CL)
monocyte
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Blood
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bp(GO:"actin cytoskeleton reorganization") negativeCorrelation bp(MESH:Phagocytosis) View Subject | View Object

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Cell Ontology (CL)
monocyte
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Blood
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bp(MESH:Phagocytosis) negativeCorrelation bp(GO:"actin cytoskeleton reorganization") View Subject | View Object

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monocyte
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Blood
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Evidence 7f9a11915c
JSON

Heme stimulation of RAW264.7 macrophages induced immediate Cdc42 activation for up to 30 min after stimulation (Fig. 6d), without inducing changes in total Cdc42 protein amounts (Supplementary Fig. 6b).

a(CHEBI:heme) increases act(p(MGI:Cdc42)) View Subject | View Object

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monocyte
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Evidence 811de1f42f
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The top performing drug identified was the antimalarial compound quinine, which fully restored phagocytosis in the presence of heme, without affecting baseline phagocytosis (Fig. 8a and Supplementary Fig. 8b,c).

a(CHEBI:quinine) positiveCorrelation bp(MESH:Phagocytosis) View Subject | View Object

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Blood
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bp(MESH:Phagocytosis) positiveCorrelation a(CHEBI:quinine) View Subject | View Object

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Evidence 0bd63f6355
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Quinine pretreatment protected RAW264.7 macrophages (Fig. 8b and Supplementary Fig. 8c,d) and human macrophages (Fig. 8c) from heme-induced inhibition of phagocytosis and actin cytoskeleton changes (Supplementary Fig. 8e,f) compared with DMSO-treated cells.

a(CHEBI:quinine) positiveCorrelation bp(MESH:Phagocytosis) View Subject | View Object

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Blood
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a(CHEBI:quinine) negativeCorrelation bp(GO:"actin cytoskeleton reorganization") View Subject | View Object

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monocyte
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Blood
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bp(GO:"actin cytoskeleton reorganization") negativeCorrelation a(CHEBI:quinine) View Subject | View Object

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bp(MESH:Phagocytosis) positiveCorrelation a(CHEBI:quinine) View Subject | View Object

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Evidence f43afd24bd
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Notably, quinine diminished the association of heme with DOCK8 without affecting the association of heme with MPP1 or LGALS3 in RAW264.7 macrophages (Fig. 8d), suggesting that quinine exerted its protective effect by specifically disrupting the heme-DOCK8 association.

a(CHEBI:quinine) decreases complex(a(CHEBI:heme), p(MGI:Dock8)) View Subject | View Object

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monocyte
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Evidence 3f675e287d
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Following induction of E. coli peritonitis in wild-type mice, quinine treatment did not affect plasma heme levels, but did lead to a reduction in bacterial counts in blood and liver (Fig. 8f,g and Supplementary Fig. 8g,h), thereby restoring the bacterial clearance capacity of heme-treated mice.

a(CHEBI:quinine) negativeCorrelation bp(MESH:"Bacterial Load") View Subject | View Object

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monocyte
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Blood
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bp(MESH:"Bacterial Load") negativeCorrelation a(CHEBI:quinine) View Subject | View Object

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monocyte
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Evidence 9e70d88d6a
JSON

Cdc42 is involved in cell motility and phagocytosis, but is mainly recognized as being a central node in the formation of lamellipodia and filopodia at the leading edge3

a(MESH:Pseudopodia) positiveCorrelation p(MGI:Cdc42) View Subject | View Object

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bp(MESH:"Cell Movement") positiveCorrelation p(MGI:Cdc42) View Subject | View Object

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monocyte
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bp(MESH:Phagocytosis) positiveCorrelation p(MGI:Cdc42) View Subject | View Object

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p(MGI:Cdc42) positiveCorrelation bp(MESH:"Cell Movement") View Subject | View Object

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monocyte
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p(MGI:Cdc42) positiveCorrelation bp(MESH:Phagocytosis) View Subject | View Object

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monocyte
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Blood
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p(MGI:Cdc42) positiveCorrelation a(MESH:Pseudopodia) View Subject | View Object

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monocyte
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Evidence e71ce05ace
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Inhibiting mDIA2 using its specific inhibitor, K216-0385, fully abrogated heme-induced filopodia extension (Fig. 6g,h and Supplementary Fig. 6c).

a(MESH:Pseudopodia) positiveCorrelation p(MGI:Diaph3) View Subject | View Object

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p(MGI:Diaph3) positiveCorrelation a(MESH:Pseudopodia) View Subject | View Object

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Evidence 72f80a2b91
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Together, these data indicate that heme induces extensive actin cytoskeleton alterations, which results in defective phagocytosis and inflammatory cell migration.

bp(GO:"actin cytoskeleton reorganization") negativeCorrelation bp(MESH:Phagocytosis) View Subject | View Object

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Cell Ontology (CL)
monocyte
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Blood
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bp(MESH:Phagocytosis) negativeCorrelation bp(GO:"actin cytoskeleton reorganization") View Subject | View Object

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monocyte
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Blood
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Evidence 7dacdd9b03
JSON

Our finding that DOCK8 is necessary for the cytoskeleton changes and disruption of bacterial phagocytosis by heme is consistent with recent studies showing that DOCK8 regulates dendritic cell migration via Cdc42 (refs. 37,44).

bp(GO:"actin cytoskeleton reorganization") positiveCorrelation p(MGI:Dock8) View Subject | View Object

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bp(MESH:Phagocytosis) negativeCorrelation p(MGI:Dock8) View Subject | View Object

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monocyte
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p(MGI:Dock8) positiveCorrelation bp(GO:"actin cytoskeleton reorganization") View Subject | View Object

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monocyte
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Blood
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p(MGI:Dock8) negativeCorrelation bp(MESH:Phagocytosis) View Subject | View Object

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Cell Ontology (CL)
monocyte
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Blood
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Evidence e461650d4b
JSON

In contrast with wild-type ER-HoxB8 BMDMs, Dock8−/− ER-HoxB8 BMDM did not spread or extend filopodia (Fig. 7a,b), and failed to activate Cdc42 following treatment with heme (Fig. 7c), indicating that DOCK8 was essential for heme-induced activation of Cdc42.

p(MGI:Dock8) positiveCorrelation p(MGI:Cdc42) View Subject | View Object

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p(MGI:Cdc42) positiveCorrelation p(MGI:Dock8) View Subject | View Object

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monocyte
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Evidence 32d4c26924
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Macrophages are crucial for the removal of excess heme resulting from hemolysis via the uptake and degradation of heme by HO-1 (ref. 23), encoded by Hmox1.

p(MGI:Hmox1) increases deg(a(CHEBI:heme)) View Subject | View Object

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