The metabolic function of pyruvate kinase M2 regulates reactive oxygen species production and microbial killing by neutrophils

Juliana Escher Toller-Kawahisa (), Carlos Hiroji Hiroki, Camila Meirelles de Souza Silva, Daniele Carvalho Nascimento, Gabriel Azevedo Públio, Timna Varela Martins, Luis Eduardo Alves Damasceno, Flávio Protásio Veras, Paula Ramos Viacava, Fábio Yuji Sukesada, Emily Anne Day, Alessia Zotta, Tristram Alexander Jasper Ryan, Rodrigo Moreira da Silva, Thiago Mattar Cunha, Norberto Peporine Lopes, Fernando de Queiroz Cunha, Luke Anthony John O’Neill and José Carlos Alves-Filho ()
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Juliana Escher Toller-Kawahisa: University of Sao Paulo
Carlos Hiroji Hiroki: University of Sao Paulo
Camila Meirelles de Souza Silva: University of Sao Paulo
Daniele Carvalho Nascimento: University of Sao Paulo
Gabriel Azevedo Públio: University of Sao Paulo
Timna Varela Martins: University of Sao Paulo
Luis Eduardo Alves Damasceno: University of Sao Paulo
Flávio Protásio Veras: University of Sao Paulo
Paula Ramos Viacava: University of Sao Paulo
Fábio Yuji Sukesada: University of Sao Paulo
Emily Anne Day: Trinity Biomedical Science Institute, Trinity College Dublin
Alessia Zotta: Trinity Biomedical Science Institute, Trinity College Dublin
Tristram Alexander Jasper Ryan: Trinity Biomedical Science Institute, Trinity College Dublin
Rodrigo Moreira da Silva: University of São Paulo
Thiago Mattar Cunha: University of Sao Paulo
Norberto Peporine Lopes: University of São Paulo
Fernando de Queiroz Cunha: University of Sao Paulo
Luke Anthony John O’Neill: Trinity Biomedical Science Institute, Trinity College Dublin
José Carlos Alves-Filho: University of Sao Paulo

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: Abstract Neutrophils rely predominantly on glycolytic metabolism for their biological functions, including reactive oxygen species (ROS) production. Although pyruvate kinase M2 (PKM2) is a glycolytic enzyme known to be involved in metabolic reprogramming and gene transcription in many immune cell types, its role in neutrophils remains poorly understood. Here, we report that PKM2 regulates ROS production and microbial killing by neutrophils. Zymosan-activated neutrophils showed increased cytoplasmic expression of PKM2. Pharmacological inhibition or genetic deficiency of PKM2 in neutrophils reduced ROS production and Staphylococcus aureus killing in vitro. In addition, this also resulted in phosphoenolpyruvate (PEP) accumulation and decreased dihydroxyacetone phosphate (DHAP) production, which is required for de novo synthesis of diacylglycerol (DAG) from glycolysis. In vivo, PKM2 deficiency in myeloid cells impaired the control of infection with Staphylococcus aureus. Our results fill the gap in the current knowledge of the importance of lower glycolysis for ROS production in neutrophils, highlighting the role of PKM2 in regulating the DHAP and DAG synthesis to promote ROS production in neutrophils.

Date: 2023
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DOI: 10.1038/s41467-023-40021-6

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