TY - JOUR
T1 - CXCR4 and MIF are required for neutrophil extracellular trap release triggered by Plasmodium-infected erythrocytes
AU - Rodrigues, Danielle A.S.
AU - Prestes, Elisa B.
AU - Gama, Andreza M.S.
AU - de Souza Silva, Leandro
AU - Pinheiro, Ana Acácia S.
AU - Ribeiro, Jose Marcos C.
AU - Campos, Raquel M.P.
AU - Pimentel-Coelho, Pedro M.
AU - de Souza, Heitor S.
AU - Dicko, Alassane
AU - Duffy, Patrick E.
AU - Fried, Michal
AU - Francischetti, Ivo M.B.
AU - Saraiva, Elvira M.
AU - Paula-Neto, Heitor A.
AU - Bozza, Marcelo T.
N1 - Funding Information:
This work was financially supported by Conselho Nacional de Pesquisa (CNPq), Coordena??o de Aperfei?oamento de Pessoal de N?vel Superior (CAPES) and Funda??o de Amparo ? Pesquisa do Rio de Janeiro (FAPERJ). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors thank Prof. Richard Bucala and Dr. Lin Leng (Yale School of Medicine) for providing anti-MIF neutralizing monoclonal antibody ascite, and members of the Bozza Lab for helpful discussions.
Funding Information:
Funding:Thisworkwasfinanciallysupportedby ConselhoNacionaldePesquisa(CNPq), Coordenac ¸ãodeAperfeic ¸oamentodePessoalde Nı ´vel Superior (CAPES) and Fundac ¸ão de Amparo à PesquisadoRiodeJaneiro(FAPERJ).Thefunders hadnoroleinstudydesign,datacollectionand
Publisher Copyright:
This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
PY - 2020/8
Y1 - 2020/8
N2 - 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.
AB - 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.
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U2 - 10.1371/JOURNAL.PPAT.1008230
DO - 10.1371/JOURNAL.PPAT.1008230
M3 - Article
C2 - 32797076
AN - SCOPUS:85090078655
VL - 16
JO - PLoS Pathogens
JF - PLoS Pathogens
SN - 1553-7366
IS - 8
M1 - e1008230
ER -