TY - JOUR
T1 - Malarial hemozoin is a Nalp3 inflammasome activating danger signal
AU - Dostert, Catherine
AU - Guarda, Greta
AU - Romero, Jackeline F.
AU - Menu, Philippe
AU - Gross, Olaf
AU - Tardivel, Aubry
AU - Suva, Mario Luca
AU - Stehle, Jean Christophe
AU - Kopf, Manfred
AU - Stamenkovic, Ivan
AU - Corradin, Giampietro
AU - Tschopp, Jurg
PY - 2009/8/4
Y1 - 2009/8/4
N2 - 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-1β. 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.
AB - 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-1β. 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.
UR - http://www.scopus.com/inward/record.url?scp=68349157477&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0006510
DO - 10.1371/journal.pone.0006510
M3 - Article
C2 - 19652710
AN - SCOPUS:68349157477
SN - 1932-6203
VL - 4
JO - PLoS ONE
JF - PLoS ONE
IS - 8
M1 - e6510
ER -