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Metabolites and the Immune System

What’s a Metabolite?
Metabolites are compounds that cells utilize to perform a variety of functions. By definition, they are small molecules (less than 1 kDa in size) with a variety of functions, including energy fuel, structural support, catalytic activity, and can exhibit either stimulatory or inhibitory effects on enzymes or other organisms.

Metabolomics, or the study of the metabolome, is a crucial field of study when examining cellular behavior. Shifts in cellular phenotype are first reflected within the metabolic processes of cells. Many scientists traditionally examine differences in proteomes/genomes/transcriptomes to quantitate changes in phenotype, but these changes are often seen first within the metabolome when compared to protein or gene expression. Metabolomics-based studies have the capability to give a more direct and immediate picture of the current cellular phenotype, but were not a feasible option until recently.


Comic by Randall Munroe
Metabolism at the cellular level is a relatively understudied field compared to other –omics fields, but it is growing rapidly. The introduction of new comprehensive metabolomic screening platforms have allowed scientists to investigate the overall metabolic process of cells in an unbiased way, and this has lead to a variety of discoveries on how many cells interact with a variety metabolites. In today’s blog post, we will focus on metabolites that have been found to interact with the immune system.

Metabolic Pathways & Cellular Phenotypes
Macrophages have been a popular target for metabolomics investigations, due to their phagocytic activity and dual role as either pro-inflammatory (M1) or anti-inflammatory (M2) cells. Recent studies have shown the metabolic profiles of M1 and M2 macrophages are highly distinct from one another, with M1 macrophages exhibiting high levels of glycolysis and pentose phosphate pathway activity, altered Krebs cycle activity, and increased fatty acid synthesis. On the other hand, M2 macrophages often display high levels of fatty acid oxidation and oxidative phosphorylation [1]. This discovery in particular is interesting because it has been historically established that high levels of lipid degradation and increased lipid metabolism are linked to several chronic inflammatory diseases, including SLE, RA and diabetes [2].

Mac the Macrophage from the Guardians of Biology
In addition to examining M1 and M2 phenotypes, cellular metabolic profiles of T cells have also been investigated to examine the differences between effector and regulatory CD4+ T cells. Effector T cells have an increased amount of Glut1 expression, which indicates an increase in glucose metabolism, whereas regulatory T cells rely more on lipid metabolism for their energy needs when compared to naïve T cells [3].

Investigating the energy cycles of specific cellular phenotypes has become a popular topic of research, but why these cells prefer certain energy-generating metabolic pathways is unclear. Future studies investigating the advantages and downstream effects of these pathways are needed.

Signaling Capabilities of Specific Metabolites

In addition to investigating overall metabolic pathways, several studies have focused on the signaling effects of specific metabolites and how they can affect cellular behavior.

Some metabolites have been shown to have immediate inflammation-related effects, but how they can trigger inflammatory pathways can vary. Palmitate, a common by-product of saturated fatty acid degradation, can activate TLR2 by promoting TLR2 to dimerize with TLR1 [4]. Conversely, polyunsaturated fatty acids such as DHA have been historically shown to have an anti-inflammatory effect, but the mechanism behind this activity is much more complex. [5]
Succinate, a Krebs cycle metabolite, can perform a variety of functions outside of the energy cycle activity, including increasing IL-1β production by stabilizing HIF-1α and stimulating dendritic cells by interacting with succinate receptor 1 (SUCNR1). Succinate can also act as a post-translational modification and alter gene expression, although the downstream effects of this modification are unclear [6].

Itaconic acid, another Krebs cycle metabolite, has been well-established as an anti-microbial metabolite that can inhibit bacterial isocitrate lyase to prevent bacterial growth, but it has also been shown to inhibit endogenous succinate dehydrogenase and can contribute to succinate accumulation. While this build-up of succinate can trigger pro-inflammatory responses by stimulating dendritic cells, itaconic acid itself is a powerful anti-inflammatory metabolite that activates Nrf2 and limits the type 1 interferon response [7].


Cartoon by Scott Metzger
In conclusion, metabolite-focused studies have allowed researchers to explore cell signaling and phenotypes in a new light, and further studies are needed to investigate the mechanism of action of these metabolites. Interested to find out how BioLegend can help your metabolomics and immunology based studies? Email us at tech@biolegend.com to learn more!

 

References:

  1. Reprogramming mitochondrial metabolism in macrophages as an anti-inflammatory signal
  2. Inflammation and metabolic disorders
  3. Cutting Edge: Distinct Glycolytic and Lipid Oxidative Metabolic Programs are Essential for Effector and Regulatory CD4+ T Cell Subsets
  4. Mechanisms for the activation of Toll-like receptor 2/4 by saturated fatty acids and inhibition by docosahexaenoic acid
  5. Omega‐3 polyunsaturated fatty acids and inflammatory processes: nutrition or pharmacology?
  6. Succinate: a metabolic signal in inflammation
  7. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1
Contributed by Samantha Stanley, PhD.
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