Heme Impairs Prostaglandin E2 and TGF-β Production by Human Mononuclear Cells via Cu/Zn Superoxide Dismutase: Insight into the Pathogenesis of Severe Malaria

Abstract

In many hemolytic disorders, such as malaria, the release of free heme has been involved in the triggering of oxidative stress and tissue damage. Patients presenting with severe forms of malaria commonly have impaired regulatory responses. Although intriguing, there is scarce data about the involvement of heme on the regulation of immune responses. In this study, we investigated the relation of free heme and the suppression of anti-inflammatory mediators such as PGE2 and TGF-β in human vivax malaria. Patients with severe disease presented higher hemolysis and higher plasma concentrations of Cu/Zn superoxide dismutase (SOD-1) and lower concentrations of PGE2 and TGF-β than those with mild disease. In addition, there was a positive correlation between SOD-1 concentrations and plasma levels of TNF-α. During antimalaria treatment, the concentrations of plasma SOD-1 reduced whereas PGE2 and TGF-β increased in the individuals severely ill. Using an in vitro model with human mononuclear cells, we demonstrated that the heme effect on the impairment of the production of PGE2 and TGF-β partially involves heme binding to CD14 and depends on the production of SOD-1. Aside from furthering the current knowledge about the pathogenesis of vivax malaria, the present results may represent a general mechanism for hemolytic diseases and could be useful for future studies of therapeutic approaches.

Association between the Haptoglobin and Heme Oxygenase 1 Genetic Profiles and Soluble CD163 in Susceptibility to and Severity of Human Malaria

“…The study sample includes 78 subjects with symptomatic malaria, 106 subjects with asymptomatic malaria, and 80 uninfected individuals. These individuals have already been analyzed by our group in other studies (1,(3)(4)(5)(6)(7). Active and passive case detections were performed using both microscopy and nested PCR.…”

“…Free heme is highly harmful to cells and tissues, as it can induce oxidative stress, cytotoxicity and inflammation (25), and cell death (30). Patients with severe malaria may exhibit high circulating levels of free heme, which impairs regulatory responses and can cause inflammatory imbalances (1). Under homeostatic conditions, haptoglobin (Hp) can rapidly scavenge cell-free Hb by forming the stable Hb-Hp complex, which is recognized and internalized by the CD163 receptor expressed by monocytes and macrophages in the red pulp of the spleen.…”

Red alert: labile heme is an alarmin

“…The authors thank Luis Ferreira Moita (Instituto Gulbenkian de Ciência) for critical review of the manuscript and Zélia Gouveia for producing the heme structures in Figure 1 Mø [59,61,62,[67][68][69] and endothelial cells [20]. In some cases this is mediated via a mechanism involving heme sensing by PRR [20,27,28] as well as G coupled proteins…”

Heme induces programmed necrosis on macrophages through autocrine TNF and ROS production

“…31,32 Heme affects cytokine and lipid mediator production by macrophages, in part through superoxide dismutase and 5-lypoxigenase. 33,34 Moreover, heme activates Toll-like receptor 4 (TLR4)-induced TNF production in macrophages. 35 Interestingly, heme induces ROS in a TLR4-independent manner.…”