Hemozoin Induces Hepatic Inflammation in Mice and Is Differentially Associated with Liver Pathology Depending on the Plasmodium Strain

Abstract

Malaria is a global disease that clinically affects more than two hundred million people annually. Despite the availability of effective antimalarials, mortality rates associated with severe complications are high. Hepatopathy is frequently observed in patients with severe malarial disease and its pathogenesis is poorly understood. Previously, we observed high amounts of hemozoin or malaria pigment in livers from infected mice. In this study, we investigated whether hemozoin is associated with liver injury in different mouse malaria models. C57BL/6J mice infected with the rodent parasites Plasmodium berghei ANKA, P. berghei NK65 or P. chabaudi AS had elevated serum liver enzymes without severe histological changes in the liver, in line with the observations in most patients. Furthermore, liver enzymes were significantly higher in serum of P. chabaudi AS-infected mice compared to mice infected with the P. berghei parasite strains and a strong positive correlation was found between hepatic hemozoin levels, hepatocyte damage and inflammation in the liver with P. chabaudi AS. The observed liver injury was only marginally influenced by the genetic background of the host, since similar serum liver enzyme levels were measured in infected C57BL/6J and BALB/c mice. Intravenous injection of P. falciparum-derived hemozoin in malaria-free C57BL/6J mice induced inflammatory gene transcription in the liver, suggesting that hemozoin may be involved in the pathogenesis of malaria hepatopathy by inducing inflammation.

Safety and Reproducibility of a Clinical Trial System Using Induced Blood Stage Plasmodium vivax Infection and Its Potential as a Model to Evaluate Malaria Transmission

“…falciparum malaria in Malawi, hemozoin-filled Kupffer cells were invariably present and thought to be the source of inflammatory signals [45]. Mouse studies suggest that hemazoin-induced inflammation is responsible for hepatic dysfunction [46], while other studies suggest that mitochondrial pathology and oxidative stress promote hepatocyte apoptosis [47]. Of note, the donor of the P .…”

The role of regulatory T cells during Plasmodium chabaudi chabaudi AS infection in BALB/c mice

“…a). P. c. chabaudi AS infection has been shown to cause liver inflammation and liver cell necrosis, which can cause death in severe cases . Therefore, we examined liver pathology and the liver index.…”

Plasmodium berghei ANKA infection results in exacerbated immune responses from C57BL/6 mice displaying hypothalamic obesity

“…Several components of the parasite might be triggering the production of these mediators. Recently, it has been described that hemozoin is a key factor in this process in the lung [15] and liver [16], raising our concern about its importance in the brain.…”