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

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.

Metabolism and acetylation in innate immune cell function and fate.

Innate immunity is the first line of defense against invading pathogens. Changes in both metabolism and chromatin accessibility contribute to the shaping of these innate immune responses, and we are beginning to appreciate that cross-talk between these two systems plays an important role in determining innate immune cell differentiation and function. In this review we focus on acetylation, a post-translational modification important for both regulating chromatin accessibility by modulating histone function, and for functional regulation of non-histone proteins, which has many links to both immune signaling and metabolism. We discuss the interactions between metabolism and acetylation, including the requirement for metabolic intermediates as substrates and co-factors for acetylation, and the regulation of metabolic proteins and enzymes by acetylation. Here we highlight recent findings, which demonstrate the role that the metabolism-acetylation axis has in coordinating the responses of innate immune cells to the availability of nutrients and the microenvironment.

Glucose represses dendritic cell-induced T cell responses.

Glucose and glycolysis are important for the proinflammatory functions of many immune cells, and depletion of glucose in pathological microenvironments is associated with defective immune responses. Here we show a contrasting function for glucose in dendritic cells (DCs), as glucose represses the proinflammatory output of LPS-stimulated DCs and inhibits DC-induced T-cell responses. A glucose-sensitive signal transduction circuit involving the mTOR complex 1 (mTORC1), HIF1α and inducible nitric oxide synthase (iNOS) coordinates DC metabolism and function to limit DC-stimulated T-cell responses. When multiple T cells interact with a DC, they compete for nutrients, which can limit glucose availability to the DCs. In such DCs, glucose-dependent signalling is inhibited, altering DC outputs and enhancing T-cell responses. These data reveal a mechanism by which T cells regulate the DC microenvironment to control DC-induced T-cell responses and indicate that glucose is an important signal for shaping immune responses.