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Review
. 2020 Apr;30(4):300-314.
doi: 10.1038/s41422-020-0291-z. Epub 2020 Mar 4.

Targeting immunometabolism as an anti-inflammatory strategy

Eva M Pålsson-McDermott  1 , Luke A J O'Neill  2
Affiliations
Review

Targeting immunometabolism as an anti-inflammatory strategy

Eva M Pålsson-McDermott et al. Cell Res. 2020 Apr.

Abstract

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.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Targeting enzymes of glycolysis as an anti-inflammatory strategy.
Inhibition of hexokinase by 2-DG and GAPDH by Heptelidic acid as well as tetramerization and activation of the pyruvate kinase activity of PKM2 by TEPP-46 has proven anti-inflammatory in several models of infection and inflammation. Targeting the glucose transporter Glut1 may also hold promise as a novel therapeutic target to limit inflammation. Glut-1 glucose transporter-1, 2-DG 2-deoxyglucose, SLE systemic lupus erythematosus, RA rheumatoid arthritis, GAPDH Glyceraldehyde 3-phosphate dehydrogenase, EAE experimental autoimmune encephalomyelitis, AKI acute kidney injury.
Fig. 2
Fig. 2. Modifying intermediates of the TCA cycle to drive an anti-inflammatory response.
Located in the mitochondrial matrix, the TCA cycle serves to break down nutrients such as glycolysis-generated pyruvate. Metabolic intermediates such as succinate, itaconate and citrate all play a role in inflammation. Enzymes include citrate synthase (CS), isocitrate dehydrogenase (IDH), aconitase (ACO2), α-ketoglutarate dehydrogenase (OGDH), succinyl-CoA synthestase, succinate dehydrogenase (SDH) which makes up Complex II of the electron transport chain, fumarase (FH), malate dehydrogenase (MDH) and Immuneresponsive gene-1 (IRG-1), also known as Aconitate Decarboxylase 1 (ACOD1), the enzyme responsible for the production of itaconate.
Fig. 3
Fig. 3. Skewering immune cells towards an anti-inflammatory phenotype using small molecules.
By modulating various metabolic pathways of proinflammatory immune cells we can promote a more anti-inflammatory phenotype. Small molecules such as DMM, TEPP-46, Rapamycin, 2DG, DMF and Hyaluronic acid all promote the development of anti-inflammatory Treg cells and M2 macrophages, whilst suppressing differentiation of the more inflammatory Th17 cells and M1 macrophages, which most likely contributes to the efficacious outcomes when using these in models of inflammatory disease.
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