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- Title
The metabolic function of pyruvate kinase M2 regulates reactive oxygen species production and microbial killing by neutrophils.
- Authors
Toller-Kawahisa, Juliana Escher; Hiroki, Carlos Hiroji; Silva, Camila Meirelles de Souza; Nascimento, Daniele Carvalho; Públio, Gabriel Azevedo; Martins, Timna Varela; Damasceno, Luis Eduardo Alves; Veras, Flávio Protásio; Viacava, Paula Ramos; Sukesada, Fábio Yuji; Day, Emily Anne; Zotta, Alessia; Ryan, Tristram Alexander Jasper; Moreira da Silva, Rodrigo; Cunha, Thiago Mattar; Lopes, Norberto Peporine; Cunha, Fernando de Queiroz; O'Neill, Luke Anthony John; Alves-Filho, José Carlos
- 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. Neutrophil activation has been shown to rely on the pentose phosphate pathway (PPP) for NADPH generation and reactive oxygen species production. In this study, the authors identify a mechanism of neutrophil activation that is independent of the PPP but relies on the glycolytic enzyme pyruvate kinase M2 instead.
- Subjects
NEUTROPHILS; PYRUVATE kinase; REACTIVE oxygen species; PENTOSE phosphate pathway; STAPHYLOCOCCUS aureus infections; MYELOID cells
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-40021-6