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

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

Research output: Contribution to journalArticle

Abstract

Severe malaria anemia is characterized by inhibited/altered erythropoiesis and presence of hemozoin-(HZ)-laden bone-marrow macrophages. HZ mediates peroxidation of unsaturated fatty acids and production of bioactive aldehydes such as 4-hydroxynonenal (HNE). HZ-laden human monocytes inhibited growth of cocultivated human erythroid cells and produced HNE that diffused to adjacent cells generating HNE-protein adducts. Cocultivation with HZ or treatment with low micromolar HNE inhibited growth of erythroid cells interfering with cell cycle without apoptosis. After HZ/HNE treatment, 2 critical proteins in cell-cycle regulation, p53 and p21, were increased and the retinoblastoma protein, central regulator of G1-to-S-phase transition, was consequently hypophosphorylated, while GATA-1, master transcription factor in erythropoiesis was reduced. The resultant decreased expression of cyclin A and D2 retarded cell-cycle progression in erythroid cells and the K562 cell line. As a second major effect, HZ and HNE inhibited protein expression of crucial receptors (R): transferrinR1, stem cell factorR, interleukin-3R, and erythropoietinR. The reduced receptor expression and the impaired cell-cycle activity decreased the production of cells expressing glycophorin-A and hemoglobin. Present data confirm the inhibitory role of HZ, identify HNE as one HZ-generated inhibitory molecule and describe molecular targets of HNE in erythroid progenitors possibly involved in erythropoiesis inhibition in malaria anemia.

Original languageEnglish
Pages (from-to)4328-4337
Number of pages10
JournalBlood
Volume116
Issue number20
DOIs
Publication statusPublished - Nov 18 2010

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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    Skorokhod, O. A., Caione, L., Marrocco, T., Migliardi, G., Barrera, V., Arese, P., Piacibello, W., & Schwarzer, E. (2010). Inhibition of erythropoiesis in malaria anemia: Role of hemozoin and hemozoin-generated 4-hydroxynonenal. Blood, 116(20), 4328-4337. https://doi.org/10.1182/blood-2010-03-272781