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Title: PFKFB2-mediated glycolysis promotes lactate-driven continual efferocytosis by macrophages.
Austin Authors: Schilperoort, Maaike;Ngai, David;Katerelos, Marina ;Power, David A ;Tabas, Ira
Affiliation: Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA.
Institute for Breathing and Sleep
Medicine (University of Melbourne)
Issue Date: 16-Feb-2023
Date: 2023
Publication information: Nature Metabolism 2023; 5(3)
Abstract: 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.
DOI: 10.1038/s42255-023-00736-8
ORCID: 0000-0002-8597-7675
Journal: Nature metabolism
PubMed URL: 36797420
ISSN: 2522-5812
Type: Journal Article
Appears in Collections:Journal articles

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