Malaria-parasitized erythrocytes and hemozoin nonenzymatically generate large amounts of hydroxy fatty acids that inhibit monocyte functions

Schwarzer, Evelin; Kühn, Hartmut; Valente, Elena; Arese, Paolo

doi:10.1182/blood-2002-03-0979

Cited by 131 publications

(151 citation statements)

References 45 publications

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“…Based on integrated peak area, a 70:1 abundance of 12-S-HETE to 12-R-HETE was observed suggesting accumulation of enzymatically produced HETE. This is in marked contrast to the equivalent stereoisomeric ratios observed for the 12-HETEs in the lipid coat of PfHz [13]. Previously, murine host 12-Lox activity has been described in the immunomodulation of schistosomiasis [32,33].…”

Section: Resultsmentioning

confidence: 68%

“…2). In contrast to previous HETE identifications in hemozoin producing parasites [13], the LC-MS/MS method presented herein is a marked advancement including MS/MS confirmation of all identified HETEs during separation and an increased instrument sensitivity reaching the femtomole range. Such a limit of detection is especially important when working with the extracted lipids of limited native Hz samples, as is the case of S. mansoni yields from Swiss-Webster mice (1 mg SmHz/60 mice).…”

Section: Resultsmentioning

confidence: 97%

“…In both cases, the lipid extracts provided a competent scaffold for hemozoin formation in vitro [22,23]. Polar hydroxylated fatty acids derived from arachidonic and linoleic acids have also been extracted from native PfHz, as has the secondary oxidation product HNE [7,13,17]. These compounds have been shown to be capable of significantly altering the function of macrophage cells during the course of malarial infection.…”

Section: Resultsmentioning

confidence: 99%

“…Schwarzer and coworkers showed that phagocytosis of native PfHz by human monocytes disrupts the normal cellular function of professional phagocytes [12,13]. The accumulation of native Hz in circulating monocytes and neutrophils inhibits normal phagocytic function by inducing oxidative stress and downregulating intercellular mechanisms that generate potent oxidative molecules used to defend against foreign invaders, namely reactive oxygen (ROS) and nitrogen species (RNS) [14].…”

Section: Introductionmentioning

confidence: 99%

“…The accumulation of native Hz in circulating monocytes and neutrophils inhibits normal phagocytic function by inducing oxidative stress and downregulating intercellular mechanisms that generate potent oxidative molecules used to defend against foreign invaders, namely reactive oxygen (ROS) and nitrogen species (RNS) [14]. Furthermore, Hz has been shown to induce lipid peroxidation of polyunsaturated fatty acids (PUFAs) resulting in the formation of potentially cytotoxic and immunomodulatory molecules including hydroxyeicosatetraenoic acids (HETEs) [7,13,15] and 4-hydroxy-2-nonenal (HNE) [16,17]. Consequently, Hz-mediated production of arachidonic acid (AA) metabolites, such as HETEs and HNE, are of significant interest in schistosomiasis since the role of Hz in the disease's pathogenesis remains largely unexplored.…”

Section: Introductionmentioning

confidence: 99%

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Identification of hydroxyeicosatetraenoic acid components of schistosomal hemozoin

Carter

Harry

Wright

2007

Biochemical and Biophysical Research Communications

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During the late stages of Schistosoma mansoni infection, adult schistosomes catabolize host erythrocytic hemoglobin. In order to evade the toxic effects of free heme, the blood fluke biomineralizes dimeric heme into an inert crystalline pigment called hemozoin. In the present study, the chemical reactivity of schistosomal hemozoin (SmHz) toward lipid oxidation was examined and the biological consequences of reactivity were investigated. Mass spectrometric analysis of polar lipid content associated with SmHz identified a variety of primary and secondary polyunsaturated fatty acid oxidation products, including hydroxyeicosatetraenoic acids. Furthermore, RAW 264.7 macrophage-like cells challenged with lipopolysaccharide prior to phagocytosis of SmHz experienced a decrease in nitric oxide production as compared to control experiments. The presence of these biologically active oxidation products suggests native SmHz is capable of modulating the innate immune response and may play a potential role in the pathogenesis of schistosomiasis.

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Section: Resultsmentioning

confidence: 68%

Section: Resultsmentioning

confidence: 97%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Identification of hydroxyeicosatetraenoic acid components of schistosomal hemozoin

Carter

Harry

Wright

2007

Biochemical and Biophysical Research Communications

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Hemozoin: A Paradigm for Biominerals in Disease

Carter

Hoang

Wright

2008

Wiley Encyclopedia of Chemical Biology

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Biomineralization is the formation of organic–inorganic composites by organisms. Originally evolved as a protective mechanism, this complex process has also become a recognized contributor to several disease states, which range from kidney stone disease (nephrolithiasis) to parasitic diseases like malaria. The characteristic three‐step process for the formation of biominerals is defined by the supramolecular preorganization of a nucleating template, the interfacial molecular recognition of crystal nuclei and the cellular processing of resultant aggregates. Hemozoin formed in the heme detoxification pathway used by the malarial parasite Plasmodium falciparum represents a paradigm for pathogenic biominerals. Current research indicates that a supramolecular lipid template organizes heme released previously during hemoglobin catabolism. Nucleation and growth of the heme aggregate serves to protect the parasite from the toxic effects of free heme. Given the mechanisms of biomineralization, it is not surprising to discover that century‐old antimalarial compounds function by disrupting key interactions between the heme substrate and template. Subsequently, the heme‐aggregate is released into the host vasculature and deposits in patients' brains, spleens, and livers where it disrupts host innate immune response. The underlying basis of this immunomodulating activity seems to result from hemozoin mediated lipid peroxidation. Understanding the relationships between hemozoin formation and its pathogenic activity with the host immune response represents a significant challenge to chemical biology.

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The biochemistry ofPlasmodium falciparum

Ginsburg

2016

Advances in Malaria Research

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Malaria-parasitized erythrocytes and hemozoin nonenzymatically generate large amounts of hydroxy fatty acids that inhibit monocyte functions

Cited by 131 publications

References 45 publications

Identification of hydroxyeicosatetraenoic acid components of schistosomal hemozoin

Identification of hydroxyeicosatetraenoic acid components of schistosomal hemozoin

Hemozoin: A Paradigm for Biominerals in Disease

The biochemistry ofPlasmodium falciparum

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