ABSTRACT
Placental malaria (PM) is associated with severe inflammation leading to abortion, preterm delivery, and intrauterine growth restriction. Innate immunity responses play critical roles, but the mechanisms underlying placental immunopathology are still unclear. Here, we investigated the role of inflammasome activation in PM by scrutinizing human placenta samples from an endemic area and ablating inflammasome components in a PM mouse model. The reduction in birth weight in babies from infected mothers is paralleled by increased placental expression of AIM2 and NLRP3 inflammasomes. Using genetic dissection, we reveal that inflammasome activation pathways are involved in the production and detrimental action of interleukin-1ß (IL-1ß) in the infected placenta. The IL-1R pharmacological antagonist Anakinra improved pregnancy outcomes by restoring fetal growth and reducing resorption in an experimental model. These findings unveil that IL-1ß-mediated signaling is a determinant of PM pathogenesis, suggesting that IL-1R antagonists can improve clinical outcomes of malaria infection in pregnancy.
Subject(s)
Inflammasomes/drug effects , Interleukin-1beta/immunology , Malaria, Falciparum/immunology , Malaria/immunology , Plasmodium falciparum/pathogenicity , Pregnancy Complications, Parasitic/immunology , Signal Transduction/drug effects , Animals , Caspase 1/genetics , Caspase 1/immunology , Cell Line , DNA-Binding Proteins/genetics , DNA-Binding Proteins/immunology , Female , Gene Expression Regulation , Humans , Immunity, Innate , Immunologic Factors/pharmacology , Inflammasomes/genetics , Inflammasomes/immunology , Interferon-gamma/genetics , Interferon-gamma/immunology , Interleukin 1 Receptor Antagonist Protein/pharmacology , Interleukin-1beta/antagonists & inhibitors , Interleukin-1beta/genetics , Malaria/drug therapy , Malaria/genetics , Malaria/parasitology , Malaria, Falciparum/genetics , Malaria, Falciparum/parasitology , Malaria, Falciparum/pathology , Mice , Mice, Knockout , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , NLR Family, Pyrin Domain-Containing 3 Protein/immunology , Plasmodium berghei/immunology , Plasmodium berghei/pathogenicity , Plasmodium falciparum/immunology , Pregnancy , Pregnancy Complications, Parasitic/genetics , Pregnancy Complications, Parasitic/parasitology , Pregnancy Complications, Parasitic/prevention & control , Receptors, Interleukin-1/genetics , Receptors, Interleukin-1/immunology , Signal Transduction/immunology , THP-1 Cells , Trophoblasts/drug effects , Trophoblasts/immunology , Trophoblasts/parasitology , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunologyABSTRACT
The use of immunosuppressive drugs guarantees the vitality of the graft and allows gestation in spite of intercurrences such as prematurity and intrauterine growth restriction. However, little is known about the direct effects of immunosuppressive drugs on placental cells. We investigated the effects of immunosuppressive drugs in the chorionic villous explants from human term placentas of healthy gestations. Human placental explants from term gestations (37-39 week gestational age, n = 12) were exposed to cyclosporine A (CSA, 0, 62.5, 125, 1250 ng/mL) or azathioprine (AZA, 0, 5, 10, 100 ng/mL) separately or, in combination for up to 48 hours. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays showed a significant decrease in the explant metabolic activity between AZA and the control group (24 hours, 100 ng/mL, 48 hours, all concentrations, P < .005). Cyclosporin A (CsA) reduced cell activity when associated with AZA (48 hours, P < .005). Fibrinoid deposits increased in AZA-treated explants alone (5 ng/mL, 48 hours; 10 ng/mL, 24-48 hours; P < .005) or when associated with CsA (10 AZA/125 CsA, P < .05), whereas in CsA treatment alone, there was an augment in syncytial knots (24-48 hours, P < .005). The sFLT1 gene (24 hours, P < .05) and protein (P < .005) expression increased in AZA and CsA-treatments separately or in combination (P < .05). Placental growth factor increased in AZA (24 hours, 10 ng/mL) and CsA (125 ng/mL; P < .05). In conclusion, our data indicate that AZA primarily acts on the villous metabolism, perturbing placental homeostasis. Since these drugs may alter the balance of angiogenic factors in its selection for clinical application, their impact on the behavior of placental villous should be considered.
