Preconditioning with Hemin Decreases Plasmodium chabaudi adami Parasitemia and Inhibits Erythropoiesis in BALB/c Mice

Abstract

Increased susceptibility to bacterial and viral infections and dysfunctional erythropoiesis are characteristic of malaria and other hemolytic hemoglobinopathies. High concentrations of free heme are common in these conditions but little is known about the effect of heme on adaptive immunity and erythropoiesis. Herein, we investigated the impact of heme (hemin) administration on immune parameters and steady state erythropoiesis in BALB/c mice, and on parasitemia and anemia during Plasmodium chabaudi adami infection. Intra-peritoneal injection of hemin (5 mg/Kg body weight) over three consecutive days decreased the numbers of splenic and bone marrow macrophages, IFN-γ responses to CD3 stimulation and Th1 differentiation. Our results show that the numbers of erythroid progenitors decreased in the bone marrow and spleen of mice treated with hemin, which correlated with reduced numbers of circulating reticulocytes, without affecting hemoglobin concentrations. Although blunted IFN-γ responses were measured in hemin-preconditioned mice, the mice developed lower parasitemia following P.c.adami infection. Importantly, anemia was exacerbated in hemin-preconditioned mice with malaria despite the reduced parasitemia. Altogether, our data indicate that free heme has dual effects on malaria pathology.

Multifaceted Role of Heme during Severe Plasmodium falciparum Infections in India

“…The degradation of the heme-hemopexin complex is likely to result in a decrease in hemopexin levels during hemolysis, thereby contributing to the systemic accumulation of heme (22). We have shown previously that intraperitoneal injections of heme in mice resulted in a decrease in hemopexin levels (10). Therefore, we propose that hemopexin levels reflect free heme levels.…”

“…During CM and malarial ARF, it is likely that the heme-mediated pathophysiology involves mechanical as well as immunological processes (8,28,29). Moreover, as a catalyzer of ROS generation, heme decreases the intracellular levels of reduced glutathione, which is associated with the modulation of the immune response through the polarization of T lymphocytes and macrophages toward T-helper 2 and M2 profiles (10,30). Cumulative evidence in our study strongly indicates an immunological network involving heme and cytokines, such as IL-10, IP-10, MCP-1, and TNF-␣, in the pathophysiology of CM and malarial ARF.…”

“…In mice, injection of heme at later stages of malarial infection triggered cerebral malaria (CM) and also was involved in hepatopathy and dyserythropoiesis (5,10,11). Interestingly, during P. vivax infections in Brazil, plasma heme levels were found to increase with disease severity (12).…”

Association of Heme Oxygenase 1 with Lung Protection in Malaria-Associated ALI/ARDS

“…It is an interesting effect, since hemin was observed to lyse malaria parasites in culture [35]. Additionally hemin treated mice infected with Plasmodium chabaudi adami also have a reduction in parasitemia [36]. Possibly, the antimalarial effect of hemin is also occurring in our model.…”

Red Blood Cells Preconditioned with Hemin Are Less Permissive to Plasmodium Invasion In Vivo and In Vitro

“…Many studies have expressed concerns about the deleterious effects of HE in the pathogenesis of malaria [ 19 , 20 ], especially since plasma hemopexin is known to be depleted in severe human malarial infection [ 10 , 21 ]. We have demonstrated a strong immune modulatory property of HE, manifested as decreased secretion of interleukin-12, sustained production of interleukin-10 by murine macrophages in vitro and blunted interferon-γ production by spleen cells in vivo [ 22 , 23 ]. These effects are known to be related to enhanced parasitemia and inhibition of the crucial Th2 helper cells/Th1 sequential polarization required to promote protective immunity against malaria [ 24 ].…”