Report Metabolic reprogramming of macrophages by PKM2 promotes IL-10 production via adenosine

Autor(es):Mostrar menos -

Toller-Kawahisa, Juliana Escher ; Viacava, Paula Ramos ; Palsson-McDermott, Eva Margareta ; Nascimento, Daniele Carvalho ; Cervantes-Silva, Mariana Patricia ; O'Carroll, Shane Myles ; Zotta, Alessia ; Damasceno, Luis Eduardo Alves ; Publio, Gabriel Azevedo ; Forti, Pedro ; Luiz, Joao Paulo Mesquita ; de Melo, Bruno Marcel Silva ; Martins, Timna Varela ; Faca, Vitor Marcel ; Curtis, Annie ; Cunha, Thiago Mattar ; Cunha, Fernando de Queiroz ; O'Neill, Luke Anthony John ; Alves-Filho, Jose Carlos

• Tipo de documento: Artigo Científico
• Fonte: CELL REPORTS; v. 44, n. 1, p. 15-pg., 2025-01-07.

Resumo

Macrophages play a crucial role in immune responses and undergo metabolic reprogramming to fulfill their functions. The tetramerization of the glycolytic enzyme pyruvate kinase M2 (PKM2) induces the production of the anti-inflammatory cytokine interleukin (IL)-10 in vivo, but the underlying mechanism remains elusive. Here, we report that PKM2 activation with the pharmacological agent TEPP-46 increases IL-10 production LPS-activated macrophages by metabolic reprogramming, leading to the production and release of ATP from glycolysis. The effect of TEPP-46 is abolished in PKM2-deficient macrophages. Extracellular ATP is converted into adenosine by ectonucleotidases that activate adenosine receptor A2a (A2aR) to enhance IL-10 production. Interestingly, IL-10 production induced by PKM2 activation is associated with improved mitochondrial health. Our results identify adenosine derived from glycolytic ATP as a driver of IL-10 production, highlighting the role of tetrameric PKM2 in regulating glycolysis to promote IL-10 production. (AU)

• Processo FAPESP: 13/08216-2 - CPDI - Centro de Pesquisa em Doenças Inflamatórias
• Beneficiário: Fernando de Queiroz Cunha
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 19/25298-9 - Papel da PKM2 no metabolismo e na função de neutrófilos
• Beneficiário: Juliana Escher Toller
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado
• Processo FAPESP: 17/01714-8 - Contribuição da PKM2 para a ativação dos neutrófilos no estabelecimento do lúpus eritematoso sistêmico experimental
• Beneficiário: Juliana Escher Toller
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado