Malarial Hemozoin Is a Nalp3 Inflammasome Activating Danger Signal

TLDR

Malaria causes recurrent fever and neurodegeneration, and its parasite produces hemozoin, a crystal formed by heme detoxification in infected red blood cells. We hypothesized that hemozoin could activate the Nalp3 inflammasome due to its particulate nature. Hemozoin activates the Nalp3 inflammasome, triggering IL‑1β release and acute peritonitis in mice, and its absence in Nalp3‑deficient animals reduces cerebral malaria severity without affecting parasitemia, while its activity is inhibited by blocking phagocytosis, K⁺ efflux, or NADPH oxidase.

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. 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.