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Malarial hemozoin is a Nalp3 inflammasome activating danger signal
Catherine Dostert1, Greta Guarda, Jackeline F Romero
1Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
Background:
Characteristic symptoms of malaria include recurrent fever attacks and neurodegeneration, signs that are also found in patients with a hyperactive Nalp3 inflammasome. Plasmodium species produce a crystal called hemozoin that is generated by detoxification of heme after hemoglobin degradation in infected red blood cells. Thus, we hypothesized that hemozoin could activate the Nalp3 inflammasome, due to its particulate nature reminiscent of other inflammasome-activating agents.
Methodology/Principal Findings:
We found that hemozoin acts as a proinflammatory danger signal that activates the Nalp3 inflammasome, causing the release of IL-1beta. Similar to other Nalp3-activating particles, hemozoin activity is blocked by inhibiting phagocytosis, K(+) efflux and NADPH oxidase. In vivo, intraperitoneal injection of hemozoin results in acute peritonitis, which is impaired in Nalp3-, caspase-1- and IL-1R-deficient mice. Likewise, the pathogenesis of cerebral malaria is dampened in Nalp3-deficient mice infected with Plasmodium berghei sporozoites, while parasitemia remains unchanged.
Significance/Conclusions:
The potent pro-inflammatory effect of hemozoin through inflammasome activation may possibly be implicated in plasmodium-associated pathologies such as cerebral malaria.
Insights
Malaria parasite byproduct, hemozoin, activates the Nalp3 inflammasome, a key inflammatory pathway. This activation may contribute to severe malaria pathologies like cerebral malaria.
Area of Science:
- Immunology
- Infectious Diseases
- Cell Biology
Background:
- Malaria symptoms like fever and neurodegeneration are linked to hyperactive Nalp3 inflammasome.
- Plasmodium parasites produce hemozoin from heme detoxification during hemoglobin breakdown in red blood cells.
Purpose of the Study:
- To investigate if hemozoin activates the Nalp3 inflammasome.
- To explore the role of hemozoin-induced inflammasome activation in malaria pathogenesis.
Main Methods:
- In vitro experiments to assess hemozoin's effect on Nalp3 inflammasome activation.
- In vivo studies using mouse models, including Nalp3-, caspase-1-, and IL-1R-deficient mice.
- Analysis of peritonitis and cerebral malaria development after hemozoin administration or Plasmodium infection.
Main Results:
- Hemozoin acts as a proinflammatory danger signal, activating the Nalp3 inflammasome and inducing IL-1beta release.
- Hemozoin's inflammasome-activating properties are dependent on phagocytosis, K(+) efflux, and NADPH oxidase.
- In vivo, hemozoin triggers acute peritonitis, which is reduced in deficient mice.
- Nalp3 deficiency dampens cerebral malaria pathogenesis without affecting parasitemia.
Conclusions:
- Hemozoin potently activates the Nalp3 inflammasome, suggesting its role in malaria-associated inflammation.
- Inflammasome activation by hemozoin may contribute to severe complications like cerebral malaria.
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