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Abstract
Malarial pigment (natural haemozoin, HZ) is a ferriprotoporphyrin 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. In a previous work HZ was shown to induce through TNFalpha production the release of monocytic lysozyme, an enzyme stored in gelatinase granules with MMP-9. Here, the underlying mechanisms were investigated. Results showed that HZ lipid moiety promoted early but not late lysozyme release. HZ-dependent lysozyme induction was abrogated by anti-TNFalpha/IL-1beta/MIP-1alpha blocking antibodies and mimicked by recombinant cytokines. Moreover, HZ early 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 induction of lysozyme release from human monocytes through activation of p38 MAPK and NF-kappaB pathways, providing new evidence on mechanisms underlying the HZ-enhanced monocyte degranulation in falciparum malaria and the potential role for lysozyme as a new affordable marker in severe malaria.
Highlights
Malaria is one of the most common parasitic diseases in the world and causes over 1 million deaths per year [1,2]
HZ early activated either p38 mitogen-activated protein kinase (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 induction of lysozyme release from human monocytes through activation of p38 MAPK and NF-kappaB pathways, providing new evidence on mechanisms underlying the HZ-enhanced monocyte degranulation in falciparum malaria and the potential role for lysozyme as a new affordable marker in severe malaria
This finding appears relevant in the context of research for early diagnosis markers of severe malaria, since plasma lysozyme levels in malaria patients have been related to disease severity [21,22]; it should be coupled with the ground-breaking evidence recently published by Kajla et al showing that in Anopheles vectors the mosquito lysozyme homologue facilitates the development of Plasmodium berghei and falciparum through direct binding to parasite oocysts [23]
Summary
Malaria is one of the most common parasitic diseases in the world and causes over 1 million deaths per year [1,2]. In a recent study we showed that 2 h after phagocytosis, HZ promoted production and release of high amounts of lysozyme [19], an antibacterial protein defined by its ability to hydrolyse beta-1,4-glycosidic linkage between Nacetylmuramic acid and N-acetylglucosamine of peptidoglycan in the cell wall of bacteria (muramidase activity) [20] This finding appears relevant in the context of research for early diagnosis markers of severe malaria, since plasma lysozyme levels in malaria patients have been related to disease severity [21,22]; it should be coupled with the ground-breaking evidence recently published by Kajla et al showing that in Anopheles vectors the mosquito lysozyme homologue facilitates the development of Plasmodium berghei and falciparum through direct binding to parasite oocysts [23]. The mechanisms underlying HZ-dependent human lysozyme enhancement in monocytes were investigated, focusing on the dependence on production of pro-inflammatory molecules and activation of p38 mitogen-activated protein kinase (MAPK) and nuclear factorkappaB (NF-kappaB) pathways
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