Mitochondrial Membrane Potential Regulates Nuclear Gene Expression in Macrophages Exposed to Prostaglandin E2

• Published in: Immunity (Cambridge, Mass.) Vol. 49; no. 6; pp. 1021 - 1033.e6
• Main Authors: Sanin, David E., Matsushita, Mai, Klein Geltink, Ramon I., Grzes, Katarzyna M., van Teijlingen Bakker, Nikki, Corrado, Mauro, Kabat, Agnieszka M., Buck, Michael D., Qiu, Jing, Lawless, Simon J., Cameron, Alanna M., Villa, Matteo, Baixauli, Francesc, Patterson, Annette E., Hässler, Fabian, Curtis, Jonathan D., O’Neill, Christina M., O’Sullivan, David, Wu, Duojiao, Mittler, Gerhard, Huang, Stanley Ching-Cheng, Pearce, Erika L., Pearce, Edward J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18.12.2018; Elsevier Limited
• Subjects: Cell activation; Cell cycle; ETS protein; ETS variant 1; ETV1; Gene expression; Gene regulation; Genes; IL-4; Immune system; immunometabolism; Interleukin 4; Laboratories; macrophage; Macrophages; Malate; malate-aspartate shuttle; Membrane potential; Metabolism; Mitochondria; mitochondrial membrane potential; Peptides; PGE2; Phosphorylation; proliferation; Prostaglandin E2; Proteins; RELMα; Software; Statistical analysis; interleukin-4; PGE2; proliferation; mitochondria; mitochondrial membrane potential; IL-4; macrophage; ETV1; ETS variant 1; immunometabolism; prostaglandin E2; malate-aspartate shuttle; RELMα
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2018.10.011

Metabolic engagement is intrinsic to immune cell function. Prostaglandin E2 (PGE2) has been shown to modulate macrophage activation, yet how PGE2 might affect metabolism is unclear. Here, we show that PGE2 caused mitochondrial membrane potential (Δψm) to dissipate in interleukin-4-activated (M(IL-4)) macrophages. Effects on Δψm were a consequence of PGE2-initiated transcriptional regulation of genes, particularly Got1, in the malate-aspartate shuttle (MAS). Reduced Δψm caused alterations in the expression of 126 voltage-regulated genes (VRGs), including those encoding resistin-like molecule α (RELMα), a key marker of M(IL-4) cells, and genes that regulate the cell cycle. The transcription factor ETS variant 1 (ETV1) played a role in the regulation of 38% of the VRGs. These results reveal ETV1 as a Δψm-sensitive transcription factor and Δψm as a mediator of mitochondrial-directed nuclear gene expression. [Display omitted] •Prostaglandin E2 (PGE2) dissipates Δψm in resting and IL-4-stimulated macrophages•PGE2-induced changes in malate-aspartate shuttle activity regulate Δψm•Δψm controls the expression of a set of genes, including Retnla, in macrophages•Δψm-dependent signaling from mitochondria to the nucleus is mediated in part by ETV1 Metabolism regulates macrophage activation. Sanin et al. demonstrate that in IL-4-activated macrophages, PGE2 induces changes in the expression of malate-aspartate shuttle genes, which in turn leads to changes in mitochondrial membrane potential and triggers alterations in chromatin accessibility and ETV1-dependent changes in expression of a gene set that includes Retnla.