Journal Article

CXCR4 and MIF are required for neutrophil extracellular trap release triggered by Plasmodium-infected erythrocytes

De Souza, Heitor S., Duffy, Patrick E., Pimentel-Coelho, Pedro M., Gama, Andreza M. S., Paula-Neto, Heitor A., Francischetti, Ivo M. B., Ribeiro, Jose Marcos C., Silva, Leandro de Souza, Fried, Michal, Saraiva, Elvira M., Dicko, Alassane, Prestes, Elisa B., Bozza, Marcelo T., Pinheiro, Ana Acácia S., Campos, Raquel M. P., Rodrigues, Danielle A. S.

2020

Overview

Neutrophil extracellular traps (NETs) evolved as a unique effector mechanism contributing to resistance against infection that can also promote tissue damage in inflammatory conditions. Malaria infection can trigger NET release, but the mechanisms and consequences of NET formation in this context remain poorly characterized. Here we show that patients suffering from severe malaria had increased amounts of circulating DNA and increased neutrophil elastase (NE) levels in plasma. We used cultured erythrocytes and isolated human neutrophils to show that Plasmodium-infected red blood cells release macrophage migration inhibitory factor (MIF), which in turn caused NET formation by neutrophils in a mechanism dependent on the C-X-C chemokine receptor type 4 (CXCR4). NET production was dependent on histone citrullination by peptidyl arginine deiminase-4 (PAD4) and independent of reactive oxygen species (ROS), myeloperoxidase (MPO) or NE. In vitro, NETs functioned to restrain parasite dissemination in a mechanism dependent on MPO and NE activities. Finally, C57/B6 mice infected with P. berghei ANKA, a well-established model of cerebral malaria, presented high amounts of circulating DNA, while treatment with DNAse increased parasitemia and accelerated mortality, indicating a role for NETs in resistance against Plasmodium infection.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Arginine / Arginine deiminase / Biology and Life Sciences / Blood / Blood cells / Cell migration / Chemokines / Citrulline / Composition / CXCR4 protein / Deoxyribonuclease / Deoxyribonucleic acid / Development and progression / DNA / Elastase / Erythrocytes / Funding / Genetic aspects / Health aspects / Immunology / Infections / Infectious diseases / Inflammation / Laboratories / Leukocyte migration / Leukocytes (neutrophilic) / Macrophage migration inhibitory factor / Malaria / Medicine and Health Sciences / Migration inhibitory factor / Neutrophils / Parasitemia / Parasites / Pathogenesis / Pathogens / Peroxidase / Physiological aspects / Plasmodium / Plasmodium falciparum / Protein-arginine deiminase / Reactive oxygen species / Red blood cells / Research and Analysis Methods / Supervision / Vector-borne diseases