title: Malarial hemozoin is a Nalp3 inflammasome activating danger signal.
abstract: 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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  The potent pro-inflammatory effect of hemozoin through inflammasome activation may possibly be implicated in plasmodium-associated pathologies such as cerebral malaria.
authors: Department of Biochemistry, University of Lausanne, Epalinges, Switzerland.
authors: Catherine
authors: C
authors: Dostert
authors: Greta
authors: G
authors: Guarda
authors: Jackeline F
authors: JF
authors: Romero
authors: Philippe
authors: P
authors: Menu
authors: Olaf
authors: O
authors: Gross
authors: Aubry
authors: A
authors: Tardivel
authors: Mario-Luca
authors: ML
authors: Suva
authors: Jean-Christophe
authors: JC
authors: Stehle
authors: Manfred
authors: M
authors: Kopf
authors: Ivan
authors: I
authors: Stamenkovic
authors: Giampietro
authors: G
authors: Corradin
authors: Jurg
authors: J
authors: Tschopp
mesh_terms: D000818:Animals; D006420:Hemeproteins / Q000502:physiology*; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D010587:Phagocytosis; D010962:Plasmodium berghei / Q000502:physiology*; D015800:Protozoan Proteins / Q000502:physiology*
chemical_list: D006420:Hemeproteins; D053583:Interleukin-1beta; D015800:Protozoan Proteins; C020753:hemozoin