Metabolic reprogramming of macrophages by PKM2 promotes IL-10 production via adenosine
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 in 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.
Authors
- Juliana E. Toller-Kawahisa (ORCID: https://orcid.org/0000-0001-7323-5036)
- José C. Alves‐Filho (ORCID: https://orcid.org/0000-0002-9918-8714)
- Luis Eduardo Alves Damasceno (ORCID: https://orcid.org/0000-0003-2833-9244)
- Alessia Zotta (ORCID: https://orcid.org/0000-0002-8274-7671)
- Thiago M. Cunha (ORCID: https://orcid.org/0000-0003-1084-0065)
- Bruno Marcel Silva de Melo (ORCID: https://orcid.org/0000-0001-7422-1445)
- Eva M. Pålsson‐McDermott (ORCID: https://orcid.org/0009-0005-0201-5171)
- Shane M. O’Carroll
- Vítor M. Faça (ORCID: https://orcid.org/0000-0003-3205-7944)
- Fernando Q. Cunha (ORCID: https://orcid.org/0000-0003-4755-1670)
- João Paulo Mesquita Luiz (ORCID: https://orcid.org/0000-0003-1878-7211)
- Daniele C. Nascimento (ORCID: https://orcid.org/0000-0002-0620-339X)
- Timna Varela Martins (ORCID: https://orcid.org/0000-0002-7939-3796)
- Annie M. Curtis (ORCID: https://orcid.org/0000-0002-9601-9624)
- Paula Ramos Viacava
- Luke O'neill (ORCID: https://orcid.org/0000-0002-4333-2748)
- Mariana P. Cervantes‐Silva
- Gabriel Azevedo Públio (ORCID: https://orcid.org/0000-0002-5643-409X)
- Pedro K K Forti
Institutions
- Royal College of Surgeons in Ireland (IE)
- Universidade de São Paulo (BR)
- Trinity College Dublin (IE)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-01-01
- DOI
- https://doi.org/10.1016/j.celrep.2024.115172
- Citations
- 29
- Primary Topic
- Adenosine and Purinergic Signaling
- Type
- article
- Field-Weighted Citation Impact
- 32.41
Funders
- Fundação de Amparo à Pesquisa do Estado de São Paulo
- Conselho Nacional de Desenvolvimento Científico e Tecnológico