Malarial Pigment Hemozoin and the Innate Inflammatory Response

Abstract

Malaria is a deadly infectious disease caused by the intraerythrocytic protozoan parasite Plasmodium. The four species of Plasmodium known to affect humans all produce an inorganic crystal called hemozoin (HZ) during the heme detoxification process. HZ is released from the food vacuole into circulation during erythrocyte lysis, while the released parasites further infect additional naive red blood cells. Once in circulation, HZ is rapidly taken up by circulating monocytes and tissue macrophages, inducing the production of pro-inflammatory mediators, such as interleukin-1β (IL-1β). Over the last few years, it has been reported that HZ, similar to uric acid crystals, asbestos, and silica, is able to trigger IL-1β production via the activation of the NOD-like receptor containing pyrin domain 3 (NLRP3) inflammasome complex. Additionally, recent findings have shown that host factors, such as fibrinogen, have the ability to adhere to free HZ and modify its capacity to activate host immune cells. Although much has been discovered regarding NLRP3 inflammasome induction, the mechanism through which this intracellular multimolecular complex is activated remains unclear. In the present review, the most recent discoveries regarding the capacity of HZ to trigger this innate immune complex as well as the impact of HZ on several other inflammatory signaling pathways will be discussed.

Malaria Parasites: The Great Escape

“…During infection, multiple parasite toxins are released at the time of iRBC rupture. These toxins include the malaria pigment, a by-product of heme degradation by the parasite (76–78), glycophosphatidylinositol (GPI) moieties that are present in many merozoite proteins, a TatD-like DNase (79), a tyrosine-tRNA synthase (80), or lipids extracted from P. vivax schizonts (81). Protection from disease by anti-toxins antibodies has been demonstrated experimentally using synthetic glycans mimicking GPI (82).…”

Liver-inherent immune system: its role in blood-stage malaria

“…Moreover, the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) is inhibited (Schwarzer et al, 1993; Prada et al, 1996) and the expression of MHC II molecules, CD54 and CD11c is impaired (Schwarzer et al, 1998). However, hemozoin does not specifically affect expression of MHC I molecules, CD16 (low affinity Fc receptor for aggregated IgG), CD64 (high affinity receptor for IgG), CD11b (receptor for complement receptor iC3b), CD35 (receptor for complement components C3b and C4b), and CD36 (non-class-A SR; Schwarzer et al, 1998; Olivier et al, 2014). More recent data indicate that hemozoin can induce the production of IL-1β through the NOD-like containing pyrin 3 domain (NLRP3) inflammasome complex (Olivier et al, 2014).…”

“…However, hemozoin does not specifically affect expression of MHC I molecules, CD16 (low affinity Fc receptor for aggregated IgG), CD64 (high affinity receptor for IgG), CD11b (receptor for complement receptor iC3b), CD35 (receptor for complement components C3b and C4b), and CD36 (non-class-A SR; Schwarzer et al, 1998; Olivier et al, 2014). More recent data indicate that hemozoin can induce the production of IL-1β through the NOD-like containing pyrin 3 domain (NLRP3) inflammasome complex (Olivier et al, 2014). These data suggest that also in vivo activities of KCs may be negatively affected by ingested hemozoin.…”

Cell death offers exceptional cellular and molecular windows for pharmacological interventions in protozoan parasites

“…Relatedly, Toxoplasma gondii infection triggers the pattern recognition receptor, NLRP3 and NLRP1 inflammasome response that is protective to the host, controlling parasite replication, dissemination and persistence [114][115][116]. Malarial hemozoin and dsDNA can be sensed as a danger signal results in the activation of the NLRP3 and absent in melanoma 2, AIM 2 inflammasome complexes respectively, which triggers pyroptosis and IL-1β and IL-18 production [117,118]. However, inflammasome activation acts as a double-edged sword for various parasitic protozoan infections.…”