title: Malarial pigment hemozoin impairs chemotactic motility and transendothelial migration of monocytes via 4-hydroxynonenal.
abstract: 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.
authors.affiliation: Department of Oncology, University of Torino, 10126 Torino, Italy.
authors.forename: Oleksii A
authors.initials: OA
authors.lastname: Skorokhod
authors.affiliation: Department of Oncology, University of Torino, 10126 Torino, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Barrera
authors.affiliation: Institute for Molecular Cell Biology, Center for Molecular Biomedicine, Friedrich Schiller University of Jena, 07745 Jena, Germany.
authors.forename: Regine
authors.initials: R
authors.lastname: Heller
authors.affiliation: Nurex srl, 07100 Sassari, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Carta
authors.affiliation: Department of Oncology, University of Torino, 10126 Torino, Italy.
authors.forename: Franco
authors.initials: F
authors.lastname: Turrini
authors.affiliation: Department of Oncology, University of Torino, 10126 Torino, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Arese
authors.affiliation: Department of Oncology, University of Torino, 10126 Torino, Italy. Electronic address: evelin.schwarzer@unito.it.
authors.forename: Evelin
authors.initials: E
authors.lastname: Schwarzer
mesh_terms: D000199:Actins / Q000378:metabolism; D000447:Aldehydes / Q000378:metabolism*; D002464:Cell Migration Inhibition / Q000187:drug effects*; D002478:Cells, Cultured; D018932:Chemokine CCL2 / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D003599:Cytoskeleton / Q000378:metabolism; D006420:Hemeproteins / Q000494:pharmacology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism*; D016778:Malaria, Falciparum / Q000276:immunology / Q000469:parasitology; D008840:Microfilament Proteins / Q000378:metabolism; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D010587:Phagocytosis / Q000502:physiology; D010860:Pigments, Biological / Q000494:pharmacology; D010963:Plasmodium falciparum / Q000201:enzymology / Q000276:immunology; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D000199:Actins; D000447:Aldehydes; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D006420:Hemeproteins; D008840:Microfilament Proteins; D010860:Pigments, Biological; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; C072061:coronin proteins; C020753:hemozoin; D009240:N-Formylmethionine Leucyl-Phenylalanine; C027576:4-hydroxy-2-nonenal
keywords: 4-Hydroxynonenal; Actin; Coronin; Free radicals; Hemozoin; Lipoperoxidation; Malaria; Migration; Monocyte