Malarial pigment (haemozoin, HZ) is a ferroprotoporphyrin IX crystal produced by Plasmodium parasites after haemoglobin catabolism. HZ-fed human monocytes are functionally compromised, releasing increased amounts of pro-inflammatory molecules, including cytokines, chemokines and cytokine-related proteolytic enzyme Matrix Metalloproteinase-9 (MMP-9), whose role in complicated malaria has been recently suggested. The present study investigated HZ effects on release of lysozyme, an enzyme stored in gelatinase granules with MMP-9, focussing on mechanisms underlying its regulation. Results showed that HZ phagocytosis by human adherent monocytes promoted early release of lysozyme, TNFalpha, IL-1beta and MIP-1alpha. HZ-enhanced lysozyme release was abrogated by anti-TNFalpha/IL-1beta/MIP-1alpha blocking antibodies and mimicked by recombinant cytokines. Moreover, HZ precociously activated either p38 MAPK or NF-kappaB pathways by inducing: p38 MAPK phosphorylation; cytosolic I-kappaBalpha phosphorylation and degradation; NF-kappaB nuclear translocation and DNA-binding. Inhibition of both routes through selected molecules (SB203580, quercetin, artemisinin, parthenolide) prevented HZ-dependent lysozyme release. These data suggest that HZ-triggered overproduction of TNFalpha, IL-1beta and MIP-1alpha mediates enhancement of lysozyme release from human monocytes through activation of p38 MAPK and NF-kappaB pathways, providing new evidence on mechanisms underlying HZ-enhanced monocyte degranulation in falciparum malaria and suggesting a potential role for lysozyme as a new affordable marker in early diagnosis of complicated malaria.

Haemozoin enhances inflammation-mediated lysozyme release from human monocytes through p38 MAPK- and NF-kappaB-dependent mechanisms.

POLIMENI, Manuela;KHADJAVI, AMINA;VALENTE, Elena;ALDIERI, Elisabetta;GIRIBALDI, Giuliana;PRATO, Mauro
2012-01-01

Abstract

Malarial pigment (haemozoin, HZ) is a ferroprotoporphyrin IX crystal produced by Plasmodium parasites after haemoglobin catabolism. HZ-fed human monocytes are functionally compromised, releasing increased amounts of pro-inflammatory molecules, including cytokines, chemokines and cytokine-related proteolytic enzyme Matrix Metalloproteinase-9 (MMP-9), whose role in complicated malaria has been recently suggested. The present study investigated HZ effects on release of lysozyme, an enzyme stored in gelatinase granules with MMP-9, focussing on mechanisms underlying its regulation. Results showed that HZ phagocytosis by human adherent monocytes promoted early release of lysozyme, TNFalpha, IL-1beta and MIP-1alpha. HZ-enhanced lysozyme release was abrogated by anti-TNFalpha/IL-1beta/MIP-1alpha blocking antibodies and mimicked by recombinant cytokines. Moreover, HZ precociously activated either p38 MAPK or NF-kappaB pathways by inducing: p38 MAPK phosphorylation; cytosolic I-kappaBalpha phosphorylation and degradation; NF-kappaB nuclear translocation and DNA-binding. Inhibition of both routes through selected molecules (SB203580, quercetin, artemisinin, parthenolide) prevented HZ-dependent lysozyme release. These data suggest that HZ-triggered overproduction of TNFalpha, IL-1beta and MIP-1alpha mediates enhancement of lysozyme release from human monocytes through activation of p38 MAPK and NF-kappaB pathways, providing new evidence on mechanisms underlying HZ-enhanced monocyte degranulation in falciparum malaria and suggesting a potential role for lysozyme as a new affordable marker in early diagnosis of complicated malaria.
2012
Malaria and British Society of Parasitology (BSP) Spring Meeting and Trypanosomiasis & Leishmaniasis Seminars
Glasgow
02-05/04/2012
Malaria and British Society of Parasitology (BSP) Spring Meeting and Trypanosomiasis & Leishmaniasis Seminars - abstract book
BSP
139
140
M. Polimeni; A. Khadjavi; E. Valente; E. Aldieri; G. Giribaldi; M. Prato
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/132220
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