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ONE-CARBON METABOLISM TUNES LIPID METABOLISM TO FACILITATE PRO-HEALING EFFEROCYTOSIS IN MACROPHAGES
Julia Drolet
*, Kentaro Takahashi, Jasmine R. Jackson, Norifumi Urao
Pharmacology, SUNY Upstate Medical University, Syracuse, NY
Macrophages play a pivotal role in tissue homeostasis and wound healing responses by clearing apoptotic cells through efferocytosis. Impaired efferocytosis is associated with conditions with non-resolving inflammation such as in metabolic syndrome, which is characterized by lower availability of the one-carbon (1C) metabolism metabolites—serine, glycine, and methionine.
To investigate the role of 1C metabolism in efferocytosis, we used oxygen controlled live cell imaging of bone marrow derived macrophages (BMDMs) co-cultured with apoptotic Jurkat cells stained with a pH-sensitive dye. BMDMs from mice fed high fat diet with L-NAME supplemented water were studied as a model of metabolic syndrome.
We found that treatment of BMDMs with serine, an amino acid and key 1C metabolite, enhanced efferocytosis under hypoxia (1% oxygen) and in pro-inflammatory (M1) BMDMs, which displayed reduced efferocytosis compared to naïve or anti-inflammatory states. Lipid droplet accumulation inversely correlated with efferocytosis, and serine supplementation reduced lipid droplet formation under both hypoxic and M1-polarized conditions. Through manipulation of culture conditions, we confirmed that serum-derived lipids were incorporated into lipid droplets. Inhibition of s-adenosyl methionine (SAM) synthesis, a 1C metabolism product and the methyl donor for methylation reactions, increased lipid droplet accumulation and reduced efferocytosis. Conversely, methionine supplementation reduced lipid droplet accumulation suggesting the importance of SAM in regulating lipid droplets and efferocytosis. In BMDMs cultured from a mouse model of metabolic syndrome, we found reduced efferocytosis, lipid droplet accumulation, and dysregulated lipid metabolism-associated gene expression. Topical serine treatment failed to enhance wound closure in diabetic mice, highlighting cell intrinsic dysregulation in diabetic wound environments.
In summary, 1C metabolism regulates macrophage lipid metabolism to facilitate efferocytosis in wound macrophages. In metabolic syndrome, limited availability of 1C metabolites and intrinsic dysregulation of lipid metabolism in macrophages may impair efferocytosis, contributing to chronic inflammation and delayed wound healing.
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