Malarial pigment hemozoin impairs chemotactic motility and transendothelial migration of monocytes via 4-hydroxynonenal

Natural hemozoin, nHZ, is avidly phagocytosed in vivo and in vitro by human monocytes. The persistence of the undigested β-hematin core of nHZ in the phagocyte lysosome for long periods of time modifies several cellular immune functions. Here we show that nHZ phagocytosis by human primary monocytes...

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Bibliographic Details
Published in:Free radical biology & medicine 2014-10, Vol.75, p.210-221
Main Authors: Skorokhod, Oleksii A., Barrera, Valentina, Heller, Regine, Carta, Franco, Turrini, Franco, Arese, Paolo, Schwarzer, Evelin
Format: Article
Language:English
Subjects:
4-Hydroxynonenal
Actin
Actins - metabolism
Aldehydes - metabolism
Cell Migration Inhibition - drug effects
Cells, Cultured
Chemokine CCL2 - pharmacology
Chemotaxis - drug effects
Coronin
Cytoskeleton - metabolism
Free radicals
Hemeproteins - pharmacology
Hemozoin
Human Umbilical Vein Endothelial Cells
Humans
Leukocytes, Mononuclear - metabolism
Lipoperoxidation
Malaria
Malaria, Falciparum - immunology
Malaria, Falciparum - parasitology
Microfilament Proteins - metabolism
Migration
Monocyte
N-Formylmethionine Leucyl-Phenylalanine - pharmacology
Phagocytosis - physiology
Pigments, Biological - pharmacology
Plasmodium falciparum - enzymology
Plasmodium falciparum - immunology
Transendothelial and Transepithelial Migration - drug effects
Tumor Necrosis Factor-alpha - pharmacology
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Summary:Natural hemozoin, nHZ, is avidly phagocytosed in vivo and in vitro by human monocytes. The persistence of the undigested β-hematin core of nHZ in the phagocyte lysosome for long periods of time modifies several cellular immune functions. Here we show that nHZ phagocytosis by human primary monocytes severely impaired their chemotactic motility toward MCP-1, TNF, and FMLP, by approximately 80% each, and their diapedesis across a confluent human umbilical vein endothelial cell layer toward MCP-1 by 45±5%. No inhibition was observed with latex-fed or unfed monocytes. Microscopic inspection revealed polarization defects in nHZ-fed monocytes due to irregular actin polymerization. Phagocytosed nHZ catalyzes the peroxidation of polyunsaturated fatty acids and generation of the highly reactive derivative 4-hydroxynonenal (4-HNE). Similar to nHZ phagocytosis, the exposure of monocytes to in vivo-compatible 4-HNE concentrations inhibited cell motility in both the presence and the absence of chemotactic stimuli, suggesting severe impairment of cytoskeleton dynamics. Consequently, 4-HNE conjugates with the cytoskeleton proteins β-actin and coronin-1A were immunochemically identified in nHZ-fed monocytes and mass spectrometrically localized in domains of protein–protein interactions involved in cytoskeleton reorganization and cell motility. The molecular and functional modifications of actin and coronin by nHZ/4-HNE may also explain impaired phagocytosis, another motility-dependent process previously described in nHZ-fed monocytes. Further studies will show whether impaired monocyte motility may contribute to the immunodepression and the frequent occurrence of secondary infections observed in malaria patients. [Display omitted] •Motility and diapedesis of human monocytes were assessed after hemozoin (HZ) feeding.•Chemotaxis, cell polarization, and actin reorganization were impaired by HZ.•4-Hydroxynonenal (4-HNE) generated in HZ-fed monocytes reproduces motility loss.•4-HNE binds to β-actin and coronin-1A, hindering actin reorganization and polarization.•Immobile phagocytes may explain superinfections and nonsterile immunity in malaria.
ISSN:0891-5849
1873-4596
DOI:10.1016/j.freeradbiomed.2014.07.004