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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. Nephrology 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. | URI: | https://ahro.austin.org.au/austinjspui/handle/1/32165 | DOI: | 10.1038/s42255-023-00736-8 | ORCID: | 0000-0002-8597-7675 0000-0003-3429-1515 |
Journal: | Nature metabolism | PubMed URL: | 36797420 | ISSN: | 2522-5812 | Type: | Journal Article |
Appears in Collections: | Journal articles |
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