Mitochondrial Membrane Potential Regulates Nuclear Gene Expression in Macrophages Exposed to PGE2 (RNA-seq)

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 causes mitochondrial membrane potential (??m) to dissipate in interleukin-4 activated macrophages (M(IL-4)). Effects on ??m are a consequence of PGE2-initiated transcriptional regulation of genes in the malate-aspartate shuttle (MAS), particularly GOT1. Reduced ??m causes alterations in the expression of 126 voltage regulated genes (VRGs) including Resistin like molecule-a (RELMa), a key marker of M(IL-4), and genes that regulate cell cycle. The transcription factor ETS variant 1 (ETV1) plays a role in the regulation of 38% of the VRGs. These results reveal ETV1 as a ??m-sensitive transcription factor, and ??m as a mediator of mitochondrial-directed nuclear gene expression. Overall design: RNA-seq was performed on bone marrow derived macrophages (triplicate) exposed to IL-4 alone or in combination with PGE2 or Valinomycin plus no stimulation controls. In addition, RNA-seq was performed on bone marrow derived macrophages stimulated in the same way as before, however the transcription factor ETV1 was knocked down.

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Sanin DE, Matsushita M, Klein Geltink RI, Grzes KM, van Teijlingen Bakker N, Corrado M, Kabat AM, Buck MD, Qiu J, Lawless SJ, Cameron AM, Villa M, Baixauli F, Patterson AE, Hässler F, Curtis JD, O'Neill CM, O'Sullivan D, Wu D, Mittler G, Huang SC, Pearce EL, Pearce EJ