Interplay of Heme with Macrophages in Homeostasis and Inflammation

Pradhan, Pooja; Vijayan, Vijith; Gueler, Faikah; Immenschuh, Stephan

doi:10.3390/ijms21030740

Cited by 33 publications

(27 citation statements)

References 106 publications

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“…Moreover, new hemolysis did not occur in this model after the initial burst (23). The prevention of complement activation could be attributed to a direct effect of Hpx, preventing the access of heme to C3 (19,24) and to an indirect, cytoprotective effect, especially on macrophages and endothelial cells (10,14,19,20,(24)(25)(26)(27). Glomerular endothelial cells are particularly vulnerable to heme-mediated complement activation in part because they are unable to overexpress HO-1 in hemolytic conditions (23,28).…”

Section: Discussionmentioning

confidence: 82%

Hemopexin as an Inhibitor of Hemolysis-Induced Complement Activation

et al. 2020

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Hemopexin is the main plasmatic scavenger of cell-free heme, released in the context of intravascular hemolysis or major cell injury. Heme is indispensable for the oxygen transport by hemoglobin but when released outside of the erythrocytes it becomes a danger-associated molecular pattern, contributing to tissue injury. One of the mechanisms of pro-inflammatory action of heme is to activate the innate immune complement cascade. Therefore, we hypothesized that injection of hemopexin will prevent hemolysis-induced complement activation. Human plasma-derived hemopexin is compatible with the heme clearance machinery of the mice. 100 or 500 mg/kg of hemopexin was injected in C57Bl/6 mice before treatment with phenylhydrazine (inducer of erythrocytes lysis) or with PBS as a control. Blood was taken at different timepoints to determine the pharmacokinetic of injected hemopexin in presence and absence of hemolysis. Complement activation was determined in plasma, by the C3 cleavage (western blot) and in the kidneys (immunofluorescence). Kidney injury was evaluated by urea and creatinine in plasma and renal NGAL and HO-1 gene expression were measured. The pharmacokinetic properties of hemopexin (mass spectrometry) in the hemolytic mice were affected by the target-mediated drug disposition phenomenon due to the high affinity of binding of hemopexin to heme. Hemolysis induced complement overactivation and signs of mild renal dysfunction at 6 h, which were prevented by hemopexin, except for the NGAL upregulation. The heme-degrading capacity of the kidney, measured by the HO-1 expression, was not affected by the treatment. These results encourage further studies of hemopexin as a therapeutic agent in models of diseases with heme overload.

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Section: Discussionmentioning

confidence: 82%

Hemopexin as an Inhibitor of Hemolysis-Induced Complement Activation

et al. 2020

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“…Heme is a crucial prosthetic group for activity of many hemoproteins, include oxygen transport, electron transport, oxygen reduction, and others ( 4 ). Heme modulates macrophage differentiation of monocytes to tissue-resident macrophages and stimulates macrophage inflammatory response ( 5 ). In sickle cell disease, heme from red cells is turned over via both intravascular and extravascular hemolysis pathways that leads to extensive pathology described in the remainder of this review.…”

Section: Introductionmentioning

confidence: 99%

The Worst Things in Life are Free: The Role of Free Heme in Sickle Cell Disease

Gbotosho¹,

Kapetanaki

Kato

2021

Front. Immunol.

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Hemolysis is a pathological feature of several diseases of diverse etiology such as hereditary anemias, malaria, and sepsis. A major complication of hemolysis involves the release of large quantities of hemoglobin into the blood circulation and the subsequent generation of harmful metabolites like labile heme. Protective mechanisms like haptoglobin-hemoglobin and hemopexin-heme binding, and heme oxygenase-1 enzymatic degradation of heme limit the toxicity of the hemolysis-related molecules. The capacity of these protective systems is exceeded in hemolytic diseases, resulting in high residual levels of hemolysis products in the circulation, which pose a great oxidative and proinflammatory risk. Sickle cell disease (SCD) features a prominent hemolytic anemia which impacts the phenotypic variability and disease severity. Not only is circulating heme a potent oxidative molecule, but it can act as an erythrocytic danger-associated molecular pattern (eDAMP) molecule which contributes to a proinflammatory state, promoting sickle complications such as vaso-occlusion and acute lung injury. Exposure to extracellular heme in SCD can also augment the expression of placental growth factor (PlGF) and interleukin-6 (IL-6), with important consequences to enthothelin-1 (ET-1) secretion and pulmonary hypertension, and potentially the development of renal and cardiac dysfunction. This review focuses on heme-induced mechanisms that are implicated in disease pathways, mainly in SCD. A special emphasis is given to heme-induced PlGF and IL-6 related mechanisms and their role in SCD disease progression.

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“…It is well-known that there is a complex interplay between hemolysis, inflammation, and erythropoiesis (87). Although intravascular hemolysis is not the main pathogenic mechanism in CHAs, it may occur in acute and severe hemolytic crisis, and results in the release of cell-free hemoglobin that has pro-inflammatory properties (88).…”

Section: Cytokine and Erythropoietin Levels In Chasmentioning

confidence: 99%

Congenital Hemolytic Anemias: Is There a Role for the Immune System?

et al. 2020

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Congenital hemolytic anemias (CHAs) are a heterogeneous group of rare hereditary conditions including defects of erythrocyte membrane proteins, red cell enzymes, and disorders due to defective erythropoiesis. They are characterized by variable degree of anemia, chronic extravascular hemolysis, reduced erythrocyte life span, splenomegaly, jaundice, biliary lithiasis, and iron overload. Although few data are reported on the role of the immune system in CHAs, several immune-mediated mechanisms may be involved in the pathogenesis of these rare diseases. We reported in ∼60% of patients with hereditary spherocytosis (HS), the presence of naturally-occurring autoantibodies (NAbs) directed against different membrane proteins (α-and β-spectrin, band 3, and dematin). Positive HS subjects showed a more hemolytic pattern and NAbs were more evident in aged erythrocytes. The latter is in line with the function of NAbs in the opsonization of damaged/senescent erythrocytes and their consequent removal in the spleen. Splenectomy, usually performed to reduce erythrocyte catheresis and improve Hb levels, has different efficacy in various CHAs. Median Hb increase is 3 g/dL in HS, 1.6-1.8 g/dL in pyruvate kinase deficiency (PKD), and 1 g/dL in congenital dyserythropoietic anemias (CDA) type II. Consistently with clinical severity, splenectomy is performed in 20% of HS, 45% of CDAII, and in 60% of PKD patients. Importantly, sepsis and thrombotic events have been registered, particularly in PKD with a frequency of ∼7% for both. Furthermore, we analyzed the role of pro-inflammatory cytokines and found that interleukin 10 and interferon γ, and to a lesser extent interleukin 6, were increased in all CHAs compared with controls. Moreover, CDAII and enzymatic defects showed increased tumor necrosis factor-α and reduced interleukin 17. Finally, we reported that iron overload occurred in 31% of patients with membrane defects, in ∼60% of CDAII cases, and in up to 82% of PKD patients (defined by MRI liver iron concentration >4 mg Fe/gdw). Hepcidin was slightly increased in CHAs compared with controls and positively correlated with ferritin and with the inflammatory cytokines interleukin 6 and interferon γ. Overall the results suggest the existence of a vicious circle between chronic hemolysis, inflammatory response, bone marrow dyserythropoiesis, and iron overload.

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Interplay of Heme with Macrophages in Homeostasis and Inflammation

Cited by 33 publications

References 106 publications

Hemopexin as an Inhibitor of Hemolysis-Induced Complement Activation

Hemopexin as an Inhibitor of Hemolysis-Induced Complement Activation

The Worst Things in Life are Free: The Role of Free Heme in Sickle Cell Disease

Congenital Hemolytic Anemias: Is There a Role for the Immune System?

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