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1.
Am J Physiol Cell Physiol ; 321(6): C1070-C1081, 2021 12 01.
Article in English | MEDLINE | ID: mdl-34705584

ABSTRACT

Mitochondria are considered to be the powerhouse of the cell. Normal functioning of the mitochondria is not only essential for cellular energy production but also for several immunomodulatory processes. Macrophages operate in metabolic niches and rely on rapid adaptation to specific metabolic conditions such as hypoxia, nutrient limitations, or reactive oxygen species to neutralize pathogens. In this regard, the fast reprogramming of mitochondrial metabolism is indispensable to provide the cells with the necessary energy and intermediates to efficiently mount the inflammatory response. Moreover, mitochondria act as a physical scaffold for several proteins involved in immune signaling cascades and their dysfunction is immediately associated with a dampened immune response. In this review, we put special focus on mitochondrial function in macrophages and highlight how mitochondrial metabolism is involved in macrophage activation.


Subject(s)
Macrophages/metabolism , Mitochondria/metabolism , Reactive Oxygen Species/metabolism , Animals , Energy Metabolism/physiology , Humans , Signal Transduction/physiology
2.
Immunity ; 51(6): 997-1011.e7, 2019 12 17.
Article in English | MEDLINE | ID: mdl-31851905

ABSTRACT

Toll-like receptor (TLR) activation induces inflammatory responses in macrophages by activating temporally defined transcriptional cascades. Whether concurrent changes in the cellular metabolism that occur upon TLR activation influence the quality of the transcriptional responses remains unknown. Here, we investigated how macrophages adopt their metabolism early after activation to regulate TLR-inducible gene induction. Shortly after TLR4 activation, macrophages increased glycolysis and tricarboxylic acid (TCA) cycle volume. Metabolic tracing studies revealed that TLR signaling redirected metabolic fluxes to generate acetyl-Coenzyme A (CoA) from glucose resulting in augmented histone acetylation. Signaling through the adaptor proteins MyD88 and TRIF resulted in activation of ATP-citrate lyase, which in turn facilitated the induction of distinct LPS-inducible gene sets. We postulate that metabolic licensing of histone acetylation provides another layer of control that serves to fine-tune transcriptional responses downstream of TLR activation. Our work highlights the potential of targeting the metabolic-epigenetic axis in inflammatory settings.


Subject(s)
ATP Citrate (pro-S)-Lyase/metabolism , Acetyl Coenzyme A/metabolism , Histones/metabolism , Macrophages/metabolism , Toll-Like Receptor 4/metabolism , Acetylation , Adaptor Proteins, Vesicular Transport/genetics , Adaptor Proteins, Vesicular Transport/metabolism , Animals , Citric Acid Cycle/physiology , Glycolysis/physiology , Humans , Lipopolysaccharides/metabolism , Macrophages/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Myeloid Differentiation Factor 88/genetics , Myeloid Differentiation Factor 88/metabolism , Signal Transduction , Transcription, Genetic/genetics
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