Triacylglycerol synthesis enhances macrophage inflammatory function

Castoldi, A.; Monteiro, L. B.; van Teijlingen Bakker, N.; Sanin, D. E.; Rana, N.; Corrado, M.; Cameron, A. M.; Hassler, F.; Matsushita, M.; Caputa, G.; Klein Geltink, R. I. I.; Buscher, J.; Edwards-Hicks, J.; Pearce, E. L.; Pearce, E. J.

doi:10.1101/2020.02.03.932079

bioRxiv · 10.1101/2020.02.03.932079

Triacylglycerol synthesis enhances macrophage inflammatory function

Castoldi, A.·Monteiro, L. B.·van Teijlingen Bakker, N.·Sanin, D. E.·Rana, N.·Corrado, M.·Cameron, A. M.·Hassler, F.·Matsushita, M.·Caputa, G.·Klein Geltink, R. I. I.·Buscher, J.·Edwards-Hicks, J.·Pearce, E. L.·Pearce, E. J.

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Abstract

Macrophages are integral to most tissues. Foam cells, macrophages with lipid droplets (LDs) which are stores of triacylglycerols (TGs) and cholesterol esters (CEs), are found in various disease states1. LDs can act as energy stores since TG lipolysis releases fatty acids (FAs) for mitochondrial oxidation (FAO), a process that relies on long-chain FA conversion into acylcarnitines by the enzyme Cpt1a2. However, in macrophages, proinflammatory signals result in diminished FAO and increased TG synthesis with LD development3,4. We explored the significance of LDs in cells that do not utilize FAO. We show that macrophages stimulated with lipopolysaccharide (LPS) plus interferon-{gamma} (IFN{gamma}) accumulate TGs in LDs, and long-chain acylcarnitines. In these cells, inhibition of TG synthesis results in diminished LD development, and increased long chain acylcarnitine levels, suggesting that FA fate is balanced between TG and acylcarnitine synthesis. Nevertheless, TG-synthesis is required for inflammatory macrophage function, since its inhibition negatively affects production of proinflammatory IL-1{beta}, IL-6 and PGE2, and phagocytic capacity, and protects against LPS-induced shock in vivo. Failure to make PGE2 is critical for this phenotype, since exogenous PGE2 reverses the anti-inflammatory effects of TG-synthesis inhibition. These findings place LDs in a position of central functional importance in inflammatory macrophages.

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Castoldi, A., Monteiro, L. B., van Teijlingen Bakker, N., Sanin, D. E., Rana, N., Corrado, M., Cameron, A. M., Hassler, F., Matsushita, M., Caputa, G., Klein Geltink, R. I. I., Buscher, J., Edwards-Hicks, J., Pearce, E. L., Pearce, E. J.. 2020-02-05. Triacylglycerol synthesis enhances macrophage inflammatory function. https://doi.org/10.1101/2020.02.03.932079

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