Macrophage Migration Inhibitory Factor Release by Macrophages after Ingestion ofPlasmodium chabaudi-Infected Erythrocytes: Possible Role in the Pathogenesis of Malarial Anemia

Abstract

Human falciparum malaria, caused by Plasmodium falciparum infection, results in 1 to 2 million deaths per year, mostly children under the age of 5 years. The two main causes of death are severe anemia and cerebral malaria. Malarial anemia is characterized by parasite red blood cell (RBC) destruction and suppression of erythropoiesis (the mechanism of which is unknown) in the presence of a robust host erythropoietin response. The production of a host-derived erythropoiesis inhibitor in response to parasite products has been implicated in the pathogenesis of malarial anemia. The identity of this putative host factor is unknown, but antibody neutralization studies have ruled out interleukin-1␤, tumor necrosis factor alpha, and gamma interferon while injection of interleukin-12 protects susceptible mice against lethal P. chabaudi infection. In this study, we report that ingestion of P. chabaudi-infected erythrocytes or malarial pigment (hemozoin) induces the release of macrophage migration inhibitory factor (MIF) from macrophages. MIF, a proinflammatory mediator and counter-regulator of glucocorticoid action, inhibits erythroid (BFU-E), multipotential (CFU-GEMM), and granulocyte-macrophage (CFU-GM) progenitor-derived colony formation. MIF was detected in the sera of P. chabaudi-infected BALB/c mice, and circulating levels correlated with disease severity. Liver MIF immunoreactivity increased concomitant with extensive pigment and parasitized RBC deposition. Finally, MIF was elevated three-to fourfold in the spleen and bone marrow of P. chabaudi-infected mice with active disease, as compared to early disease, or of uninfected controls. In summary, the present results suggest that MIF may be a host-derived factor involved in the pathophysiology of malaria anemia.Malaria is a disease caused by an intracellular parasitic protozoa of the genus Plasmodium and is transmitted by the infected female Anopheles mosquito during blood meals. Malaria is still a major cause of death and severe illness in most of the world, with 300 to 500 million new infections per year resulting in approximately 1 to 2 million deaths, mostly in children under the age of 5 years (28). The complications of severe anemia and cerebral malaria are the major causes of morbidity and mortality due to malaria. Of the four strains which infect humans, Plasmodium falciparum is the most prevalent and accounts for most malaria-related deaths.The P. falciparum life cycle includes a nonpathogenic, asymptomatic hepatic stage (extraerythrocytic), which is followed by the invasion of mature erythrocytes by infective forms (merozoites) and the initiation of the pathogenic intraerythrocytic stages. The intraerythrocytic parasite derives most of its amino acid requirements from host hemoglobin catabolism within a specialized acidic organelle, the food vacuole (19). Heme is released during hemoglobin digestion and rendered nontoxic by cross-linking into an insoluble polymer, hemozoin, through a parasite-specific biochemical activity (44). The fate of hemozoin is conne...

Malarial anemia: of mice and men

“…85,86 Conversely, with elevated levels found during infection, MIF has been shown to suppress hematopoiesis, 87 and more recently P chabaudi infection of MIF knock-out mice resulted in a less severe anemia with improved development of erythroid progenitors in the bone marrow. 88 In this latter study, a hyperparasitemic model of malaria (P chabaudi AS in Balb/c) was used.…”

Novel Anti-inflammatory Activity of Epoxyazadiradione against Macrophage Migration Inhibitory Factor

“…The ethnopharmacological exploration and bioactivity testing of various neem compounds and extracts revealed its efficacy to prevent a wide variety of inflammatory disorders in infectious and non-infectious diseases (34, [37][38][39][40][41][42][43][44][45]. It is interesting to note that neem compounds show a beneficial effect in pathological conditions in which MIF-mediated pathologies are prevalent (6,10,11,14,16,17,21).…”

“…Higher levels of MIF have been found both systemically and within affected tissues in patients with multiple sclerosis, sepsis, diabetes mellitus, glomerulonephritis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus, atherosclerosis, inflammatory bowel disease, Guillain-Barré syndrome, neuro-Behçet disease, malarial anemia, gastric ulcer, Parkinson disease, hepatocellular carcinoma, breast cancer, and bladder urothelial cell carcinoma (9 -17). MIF also has a role in deter-mining the outcome of infections caused by different parasites, bacteria, and viruses such as helminths (18), Leishmania (19), nematodes (20), malaria (21), Streptococcus (22), and dengue virus (23). Block of endogenous MIF by a small molecule such as (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) or sulforaphane and neutralization of MIF by anti-MIF antibodies or by plant-derived MIF inhibitors reduces the manifestations of immune inflammatory disorders in numerous preclinical models such as type II collagen-induced arthritis, immunologically induced kidney disease, experimental autoimmune encephalomyelitis, experimental allergic neuritis, immunoinflammatory diabetes, experimental autoimmune myocarditis, irradiation-induced acute pneumonitis, sepsis, and ischemia-reperfusion injury (14, 24 -27).…”

Anemia in Elderly Patients: An Emerging Problem for the 21st Century

“…Furthermore, both MIF and TNF␣ have been shown to impair erythroid colony formation, and MIF has been implicated in the pathogenesis of anemia associated with malaria. 15 The TNF␣, IL-6, MIF, and IL-1ß genes have functional polymorphisms that affect the level of cytokine expression. 11,16 TNF␣ polymorphisms have been linked to susceptibility to severe malarial anemia 17 and lepromatous leprosy, 18 and may predict the response to anti-TNF treatment in rheumatoid arthritis.…”