Inhibition of erythropoiesis in malaria anemia: role of hemozoin and hemozoin-generated 4-hydroxynonenal

Skorokhod, Oleksii A.; Caione, Luisa; Marrocco, Tiziana; Migliardi, Giorgia; Barrera, Valentina; Arese, Paolo; Piacibello, Wanda; Schwarzer, Evelin

doi:10.1182/blood-2010-03-272781

Cited by 90 publications

(103 citation statements)

References 46 publications

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“…6,8,19 Inhibitory effects, such as inhibition of erythropoiesis, 7 dendritic cell maturation, 19 antigen presentation, 6 and abrogation of the ability to kill ingested bacteria 3 and to repeat phagocytic cycles, 8 are long-term effects that typically start 4-6 hours after completion of phagocytosis and may persist during several days. 7,16,18 Short-term stimulatory effects 5,8 elicited by yet undisclosed mechanisms were occasionally described but have received little attention so far.…”

Section: Discussionmentioning

confidence: 99%

“…[11][12][13] Finally, short-term FG effects appear to be the starting event leading to the persistent long-term effects described in previous studies and largely mediated by HZ-generated lipoperoxidation products such as 15(S,R)-hydroxy-6,8,11,13-eicosatetraenoic acid 4,18,19 and 4-hydroxynonenal (4-HNE). 7 FG is a large 340-kDa plasma glycoprotein formed by 2 identical sets of disulfide-bridged ␣-/␤-/␥-chains. 20 In addition to its role in hemostasis, FG has been proposed as a bridging molecule for intercellular adhesions and, more importantly, as a regulator of the innate immune response.…”

Section: Discussionmentioning

confidence: 99%

“…Most functional alterations were long-term postphagocytic effects. 3,[5][6][7][8] Some of those long-term effects were also reported in human and murine phagocytes fed with BH or variously manipulated HZ. 9,10 By contrast, a powerful, short-term stimulation of oxidative burst by human monocytes was also shown to occur during phagocytosis of nHZ.…”

Section: Introductionmentioning

confidence: 99%

“…Peripheral blood mononuclear cells (PBMCs) were isolated as described [6][7][8] and either kept in suspension at 1 ϫ 10 8 cells/mL macrophage serum-free medium (M-SFM) or plated at 1 ϫ 10 7 cells/mL RPMI 1640 medium/well in 24-well plates (Falcon; Becton Dickinson). The plates were incubated in a humidified CO 2 /air incubator at 37°C for 30 minutes, and nonadherent cells were removed by 3 washes.…”

Section: Monocyte Preparationmentioning

confidence: 99%

“…[6][7][8] When indicated, HZ was isolated from plasma-free, serum-, or Albumax-supplemented cultures. The opsonized nHZ batches were tested for lipopolysaccharide (LPS) by the E-Toxate assay from Sigma (Limulus Amebocyte Lysate; gel solidification assay), sensitivity threshold at 0.05-0.1 EU/mL, and by the Limulus Amebocyte Lysate (kinetic chromogenic assay; Lonza, European Endotoxin Testing Service) with a sensitivity threshold at 0.005 EU/mL.…”

Section: Preparation and Opsonization Of Hz Rbs Bh And Rbcsmentioning

confidence: 99%

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Host fibrinogen stably bound to hemozoin rapidly activates monocytes via TLR-4 and CD11b/CD18-integrin: a new paradigm of hemozoin action

Barrera

Skorokhod

Baci

et al. 2011

Blood

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Natural hemozoin (nHZ), prepared after schizogony, consists of crystalline ferriprotoporphyrin-IX dimers from undigested heme bound to host and parasite proteins and lipids. Phagocytosed nHZ alters important functions of host phagocytes. Most alterations are long-term effects. We show that host fibrinogen (FG) was constantly present (at ϳ 1 FG per 25 000 HZ-heme molecules) and stably bound to nHZ from plasma-cultured parasites. FG was responsible for the rapid 100-fold stimulation of reactive oxygen species production and 50-fold increase of TNF and monocyte chemotactic protein 1 by human monocytes. Those effects, starting within minutes after nHZ cell contact, were because of interaction of FG with FG-receptors TLR4 and integrin CD11b/CD18. Receptor blockage by specific mAbs or removal of FG from nHZ abrogated the effects. nHZ-opsonizing IgGs contribute to the stimulatory response but are not essential for FG effects. Immediate increase in reactive oxygen species and TNF may switch on previously described long-term effects of nHZ, largely because of HZ-generated lipo-peroxidation products 15(S,R)-hydroxy-6,8,11,13-eicosatetraenoic acid and 4-hydroxynonenal. The FG/HZ effects mediated by TLR4/integrins represent a novel paradigm of nHZ activity and allow expansion of nHZ effects to nonphagocytic cells, such as endothelia and airway epithelia, and lead to a better understanding of organ pathology in malaria. (Blood. 2011;117(21):5674-5682) IntroductionNatural hemozoin (nHZ), as present in the food vacuole of Plasmodium falciparum and largely coincident with residual bodies (RBs) shed during schizogony, consists of a scaffold of crystalline ferriprotoporphyrin IX dimers (␤-hematin, BH) from undigested host hemoglobin-heme 1 bound to a vast array of host and parasite molecules. [2][3][4] nHZ is phagocytosed in vivo and in vitro by host phagocytes and alters important functions in those cells. Most functional alterations were long-term postphagocytic effects. 3,[5][6][7][8] Some of those long-term effects were also reported in human and murine phagocytes fed with BH or variously manipulated HZ. 9,10 By contrast, a powerful, short-term stimulation of oxidative burst by human monocytes was also shown to occur during phagocytosis of nHZ. 8 Here, we show that host fibrinogen (FG) was constantly present and stably bound to nHZ and RBs prepared from parasites cultured in presence of plasma. FG in nHZ was responsible for a prephagocytic rapid and powerful stimulation of oxidative burst, accompanied by release of TNF and monocyte chemotactic protein 1 (MCP-1) by human monocytes. Those prephagocytic events were because of the interaction of FG with TLR4 and integrin CD11b/CD18 (CR3, Mac-1), known receptors for FG as an immune-active molecule. [11][12][13] Present data are the first indication that nHZ-bound FG may act as a powerful self-signal molecule for early immune responses and a trigger for the persistent long-term effects that play multiple roles in malaria pathogenesis. Methods ReagentsUnless otherwise stated, reagen...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Monocyte Preparationmentioning

confidence: 99%

Section: Preparation and Opsonization Of Hz Rbs Bh And Rbcsmentioning

confidence: 99%

See 3 more Smart Citations

Host fibrinogen stably bound to hemozoin rapidly activates monocytes via TLR-4 and CD11b/CD18-integrin: a new paradigm of hemozoin action

Barrera

Skorokhod

Baci

et al. 2011

Blood

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Iron Deficiency, Iron Overload and Therapy

Crichton

2016

Iron Metabolism

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Epigenetic regulation of megakaryocytic and erythroid differentiation by PHF2 histone demethylase

Yang

Xiong

et al. 2018

Journal Cellular Physiology

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Plant homeodomain finger 2 (PHF2) is a JmjC family histone demethylase that demethylates H3K9me2, a repressive gene marker. PHF2 was found to play a role in the differentiation of several tissue types such as osteoblast and adipocyte differentiation. We report here that PHF2 plays a role in the epigenetic regulation of megakaryocytic (MK) and erythroid differentiation. We investigated PHF2 expression during MK and erythroid differentiation in K562 and human CD34 progenitor (hCD34 ) cells. Our data demonstrate that PHF2 expression is down-regulated during megakaryopoiesis and erythropoiesis. PHF2 has a negative role in MK and erythroid differentiation of K562 cells; knockdown of PHF2 promotes MK and erythroid differentiation of hCD34 cells. Similarly, we found that p53 expression is also down-regulated during MK and erythroid differentiation, which parallels PHF2 expression. PHF2 binds to the p53 promoter and regulates the expression of p53 by demethylating H3K9me2 in the promoter region of p53. Taken together, our data show that PHF2 is a negative epigenetic regulator of MK and erythroid differentiation, and that one of the pathways through which PHF2 affects MK and erythroid differentiation is via regulation of p53 expression.

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Inhibition of erythropoiesis in malaria anemia: role of hemozoin and hemozoin-generated 4-hydroxynonenal

Cited by 90 publications

References 46 publications

Host fibrinogen stably bound to hemozoin rapidly activates monocytes via TLR-4 and CD11b/CD18-integrin: a new paradigm of hemozoin action

Host fibrinogen stably bound to hemozoin rapidly activates monocytes via TLR-4 and CD11b/CD18-integrin: a new paradigm of hemozoin action

Iron Deficiency, Iron Overload and Therapy

Epigenetic regulation of megakaryocytic and erythroid differentiation by PHF2 histone demethylase

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