Hempelmann et al.[1] offer new insights into the birth and infancy of hemozoin (HZ). We found their Fig. 3 particularly interesting because it drives attention to the intimate relationship between HZ and membrane remnants, which are evidently rich in complex lipids. Membrane phospholipids are the most efficient seeds to start the biocrystallization of ferric heme [2,3] and, in native HZ (NHZ), the crystalline polyheme core is closely and stably associated with erythrocytic and parasitic membrane lipids and proteins. NHZ is phagocytosed or engulfed by phagocytes, platelets and endothelia, and the HZ stays in these cells comfortably for as long as the host cells live because even macrophages, which can catabolize heme, are unable to digest HZ [4]. Thus, phospholipids seem to represent the midwives and lifelong companions of HZ. Membrane phospholipids are modified by their intimate contact with HZ in trophozoites and in NHZ. We have recently found [5] that 1.26% and 1.15% polyunsaturated fatty acids (PUFA) stably attached to HZ in trophozoites and NHZ were transformed into hydroxy-PUFA (OH-PUFA) [5]. Such amounts of OH-PUFA, the hallmarks of lipid peroxidation, were only observed in severely peroxidized membranes. Separation and analysis of OH-PUFA in NHZ indicated 12-hydroxyarachidonic acid (12-HETE) as the major product in trophozoites, and hydroxylinoleic acid isomers 9- and 13-HODE as predominant compounds in NHZ. NHZ was also rich in 4-hydroxynonenal. Phagocytosis of NHZ or trophozoites was shown to inhibit or modulate important functions in monocytes [6], endothelia and possibly other cells types such as dendritic cells (E. Schwarzer et al., unpublished). De-lipidized NHZ did not inhibit monocyte functions such as oxidative burst, whereas selected OH-PUFAs or 4-hydroxynonenal mimicked the toxicity of NHZ on monocytes [5]. Free polymeric heme or HZ are also able to generate by heme catalysis a vast number of complex and potent molecules such as prostaglandins PGE2 and PGF2a[7,8]. Recently, it has been reported that PGE2 and PGF2a were produced by Plasmodium falciparum-infected erythrocytes [9] and by other HZ-forming parasites, such as Schistosoma mansoni, without apparent evidence of cycloxygenase activity [10]. Prostaglandins have important roles in parasitic infections [10] and they contribute significantly to parasite-induced immunodepression, for example, by inhibiting macrophage, T-cell and B-cell functions, and favoring a T helper cell type 2 response which, in certain parasitic infections, does not offer protection [11]. Thus, it is plausible to assume that OH-PUFA, prostaglandins and other disclosed and undisclosed lipid derivatives are generated non-enzymatically by heme catalysis in HZ-forming organisms, and that they could exert manifold effects in parasites and their hosts. In conclusion, HZ is much more than the elegant crystals shown in Fig. 1 of [1], and the adult career of HZ has many hidden faces to reveal.
The hidden faces of hemozoin and its dangerous midwives.
KEILING, BRIGITTE EVELIN;ARESE, Paolo
2003-01-01
Abstract
Hempelmann et al.[1] offer new insights into the birth and infancy of hemozoin (HZ). We found their Fig. 3 particularly interesting because it drives attention to the intimate relationship between HZ and membrane remnants, which are evidently rich in complex lipids. Membrane phospholipids are the most efficient seeds to start the biocrystallization of ferric heme [2,3] and, in native HZ (NHZ), the crystalline polyheme core is closely and stably associated with erythrocytic and parasitic membrane lipids and proteins. NHZ is phagocytosed or engulfed by phagocytes, platelets and endothelia, and the HZ stays in these cells comfortably for as long as the host cells live because even macrophages, which can catabolize heme, are unable to digest HZ [4]. Thus, phospholipids seem to represent the midwives and lifelong companions of HZ. Membrane phospholipids are modified by their intimate contact with HZ in trophozoites and in NHZ. We have recently found [5] that 1.26% and 1.15% polyunsaturated fatty acids (PUFA) stably attached to HZ in trophozoites and NHZ were transformed into hydroxy-PUFA (OH-PUFA) [5]. Such amounts of OH-PUFA, the hallmarks of lipid peroxidation, were only observed in severely peroxidized membranes. Separation and analysis of OH-PUFA in NHZ indicated 12-hydroxyarachidonic acid (12-HETE) as the major product in trophozoites, and hydroxylinoleic acid isomers 9- and 13-HODE as predominant compounds in NHZ. NHZ was also rich in 4-hydroxynonenal. Phagocytosis of NHZ or trophozoites was shown to inhibit or modulate important functions in monocytes [6], endothelia and possibly other cells types such as dendritic cells (E. Schwarzer et al., unpublished). De-lipidized NHZ did not inhibit monocyte functions such as oxidative burst, whereas selected OH-PUFAs or 4-hydroxynonenal mimicked the toxicity of NHZ on monocytes [5]. Free polymeric heme or HZ are also able to generate by heme catalysis a vast number of complex and potent molecules such as prostaglandins PGE2 and PGF2a[7,8]. Recently, it has been reported that PGE2 and PGF2a were produced by Plasmodium falciparum-infected erythrocytes [9] and by other HZ-forming parasites, such as Schistosoma mansoni, without apparent evidence of cycloxygenase activity [10]. Prostaglandins have important roles in parasitic infections [10] and they contribute significantly to parasite-induced immunodepression, for example, by inhibiting macrophage, T-cell and B-cell functions, and favoring a T helper cell type 2 response which, in certain parasitic infections, does not offer protection [11]. Thus, it is plausible to assume that OH-PUFA, prostaglandins and other disclosed and undisclosed lipid derivatives are generated non-enzymatically by heme catalysis in HZ-forming organisms, and that they could exert manifold effects in parasites and their hosts. In conclusion, HZ is much more than the elegant crystals shown in Fig. 1 of [1], and the adult career of HZ has many hidden faces to reveal.
I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
