PFKFB2-mediated glycolysis promotes lactate-driven continual efferocytosis by macrophages.
Journal
Nature metabolism
ISSN: 2522-5812
Titre abrégé: Nat Metab
Pays: Germany
ID NLM: 101736592
Informations de publication
Date de publication:
03 2023
03 2023
Historique:
received:
16
08
2022
accepted:
03
01
2023
pmc-release:
01
03
2024
medline:
29
3
2023
pubmed:
17
2
2023
entrez:
16
2
2023
Statut:
ppublish
Résumé
Resolving-type macrophages prevent chronic inflammation by clearing apoptotic cells through efferocytosis. These macrophages are thought to rely mainly on oxidative phosphorylation, but emerging evidence suggests a possible link between efferocytosis and glycolysis. To gain further insight into this issue, we investigated molecular-cellular mechanisms involved in efferocytosis-induced macrophage glycolysis and its consequences. We found that efferocytosis promotes a transient increase in macrophage glycolysis that is dependent on rapid activation of the enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 2 (PFKFB2), which distinguishes this process from glycolysis in pro-inflammatory macrophages. Mice transplanted with activation-defective PFKFB2 bone marrow and then subjected to dexamethasone-induced thymocyte apoptosis exhibit impaired thymic efferocytosis, increased thymic necrosis, and lower expression of the efferocytosis receptors MerTK and LRP1 on thymic macrophages compared with wild-type control mice. In vitro mechanistic studies revealed that glycolysis stimulated by the uptake of a first apoptotic cell promotes continual efferocytosis through lactate-mediated upregulation of MerTK and LRP1. Thus, efferocytosis-induced macrophage glycolysis represents a unique metabolic process that sustains continual efferocytosis in a lactate-dependent manner. The differentiation of this process from inflammatory macrophage glycolysis raises the possibility that it could be therapeutically enhanced to promote efferocytosis and resolution in chronic inflammatory diseases.
Identifiants
pubmed: 36797420
doi: 10.1038/s42255-023-00736-8
pii: 10.1038/s42255-023-00736-8
pmc: PMC10050103
mid: NIHMS1876425
doi:
Substances chimiques
c-Mer Tyrosine Kinase
EC 2.7.10.1
Lactic Acid
33X04XA5AT
Pfkfb2 protein, mouse
EC 2.7.1.105
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
431-444Subventions
Organisme : NHLBI NIH HHS
ID : R35 HL145228
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL127464
Pays : United States
Organisme : NHLBI NIH HHS
ID : P01 HL087123
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2023. The Author(s), under exclusive licence to Springer Nature Limited.
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