In recent years a substantial number of findings have been made in the area of immunometabolism, by which we mean the changes in intracellular metabolic pathways in immune cells that alter their ...function. Here, we provide a brief refresher course on six of the major metabolic pathways involved (specifically, glycolysis, the tricarboxylic acid (TCA) cycle, the pentose phosphate pathway, fatty acid oxidation, fatty acid synthesis and amino acid metabolism), giving specific examples of how precise changes in the metabolites of these pathways shape the immune cell response. What is emerging is a complex interplay between metabolic reprogramming and immunity, which is providing an extra dimension to our understanding of the immune system in health and disease.
Activation of macrophages and dendritic cells （DCs） by pro-inflammatory stimuli causes them to undergo a metabolic switch towards glycolysis and away from oxidative phosphorylation （OXPHOS）, similar ...to the Warburg effect in tumors. However, it is only recently that the mechanisms responsible for this metabolic reprogramming have been elucidated in more detail. The transcription factor hypoxia-inducible factor-la （HIF-la） plays an important role un- der conditions of both hypoxia and normoxia. The withdrawal of citrate from the tricarboxylic acid （TCA） cycle has been shown to be critical for lipid biosynthesis in both macrophages and DCs. Interference with this process actually abolishes the ability of DCs to activate T cells. Another TCA cycle intermediate, succinate, activates HIF-la and pro- motes inflammatory gene expression. These new insights are providing us with a deeper understanding of the role of metabolic reprogramming in innate immunity.
Itaconate is one of the best examples of the consequences of metabolic reprogramming during immunity. It is made by diverting aconitate away from the tricarboxylic acid cycle during inflammatory ...macrophage activation. The main reason macrophages exhibit this response currently appears to be for an anti-inflammatory effect, with itaconate connecting cell metabolism, oxidative and electrophilic stress responses and immune responses. A role for itaconate in the regulation of type I interferons during viral infection has also been described, as well as in M2 macrophage function under defined circumstances. Finally, macrophage-specific itaconate production has also been shown to have a pro-tumour effect. All of these studies point towards itaconate being a critical immunometabolite that could have far-reaching consequences for immunity, host defence and tumorigenesis.
The discovery of Toll-like receptors (TLRs) was an important event for immunology research and was recognized as such with the awarding of the 2011 Nobel Prize in Physiology or Medicine to Jules ...Hoffmann and Bruce Beutler, who, together with Ralph Steinman, the third winner of the 2011 Nobel Prize and the person who discovered the dendritic cell, were pioneers in the field of innate immunity. TLRs have a central role in immunity - in this Timeline article, we describe the landmark findings that gave rise to this important field of research.
A striking change has happened in the field of immunology whereby specific metabolic processes have been shown to be a critical determinant of immune cell activation. Multiple immune receptor types ...rewire metabolic pathways as a key part of how they promote effector functions. Perhaps surprisingly for immunologists, the Krebs cycle has emerged as the central immunometabolic hub of the macrophage. During proinflammatory macrophage activation, there is an accumulation of the Krebs cycle intermediates succinate and citrate, and the Krebs cycle-derived metabolite itaconate. These metabolites have distinct nonmetabolic signaling roles that influence inflammatory gene expression. A key bioenergetic target for the Krebs cycle, the electron transport chain, also becomes altered, generating reactive oxygen species from Complexes I and III. Similarly, alternatively activated macrophages require α-ketoglutarate-dependent epigenetic reprogramming to elicit anti-inflammatory gene expression. In this review, we discuss these advances and speculate on the possibility of targeting these events therapeutically for inflammatory diseases.
The growing field of immunometabolism has taught us how metabolic cellular reactions and processes not only provide a means to generate ATP and biosynthetic precursors, but are also a way of ...controlling immunity and inflammation. Metabolic reprogramming of immune cells is essential for both inflammatory as well as anti-inflammatory responses. Four anti-inflammatory therapies, DMF, Metformin, Methotrexate and Rapamycin all work by affecting metabolism and/or regulating or mimicking endogenous metabolites with anti-inflammatory effects. Evidence is emerging for the targeting of specific metabolic events as a strategy to limit inflammation in different contexts. Here we discuss these recent developments and speculate on the prospect of targeting immunometabolism in the effort to develop novel anti-inflammatory therapeutics. As accumulating evidence for roles of an intricate and elaborate network of metabolic processes, including lipid, amino acid and nucleotide metabolism provides key focal points for developing new therapies, we here turn our attention to glycolysis and the TCA cycle to provide examples of how metabolic intermediates and enzymes can provide potential novel therapeutic targets.
Metabolic regulation of NLRP3 Hughes, Mark M.; O'Neill, Luke A.J.
Immunological reviews,
January 2018, Letnik:
281, Številka:
1
Journal Article
Recenzirano
Summary
A shift in our understanding of macrophage biology has come about as a result of recent discoveries in the area of metabolic reprogramming of macrophages. The NLRP3 inflammasome drives the ...activation of caspase‐1, leading to the production of IL‐1β, IL‐18, and a type of cell death termed pyroptosis. The NLRP3 inflammasome has been shown to sense metabolites such as palmitate, uric acid, and cholesterol crystals and is inhibited by ketone bodies produced during metabolic flux. The NLRP3 inflammasome has also been shown to be regulated by mitochondrial reactive oxygen species and components of glycolysis, such as Hexokinase. Here, we review these findings and discuss their importance for inflammation and furthermore discuss potential therapeutic benefits of targeting NLRP3.
Macrophages undergo metabolic rewiring during polarization but details of this process are unclear. In this issue of Immunity, Jha et al. (2015) report a systems approach for unbiased analysis of ...cellular metabolism that reveals key metabolites and metabolic pathways required for distinct macrophage polarization states.
Macrophages undergo metabolic rewiring during polarization but details of this process are unclear. Jha et al. report a systems approach for unbiased analysis of cellular metabolism that reveals key metabolites and metabolic pathways required for distinct macrophage polarization states.
Metabolism in immune cells is no longer thought of as merely a process for adenosine triphosphate (ATP) production, biosynthesis, and catabolism. The reprogramming of metabolic pathways upon ...activation is also for the production of metabolites that can act as immune signaling molecules. Activated dendritic cells (DCs) and macrophages have an altered Krebs cycle, one consequence of which is the accumulation of both citrate and succinate. Citrate is exported from the mitochondria
the mitochondrial citrate- carrier. Cytosolic metabolism of citrate to acetyl-coenzyme A (acetyl-CoA) is important for both fatty-acid synthesis and protein acetylation, both of which have been linked to macrophage and DC activation. Citrate-derived itaconate has a direct antibacterial effect and also has been shown to act as an anti-inflammatory agent, inhibiting succinate dehydrogenase. These findings identify citrate as an important metabolite for macrophage and DC effector function.
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