The Importance of Metabolism for Immune Homeostasis in Allergic Diseases

Abstract

There is increasing evidence that the metabolic status of T cells and macrophages is associated with severe phenotypes of chronic inflammation, including allergic inflammation. Metabolic changes in immune cells have a crucial role in their inflammatory or regulatory responses. This notion is reinforced by metabolic diseases influencing global energy metabolism, such as diabetes or obesity, which are known risk factors of severity in inflammatory conditions, due to the metabolic-associated inflammation present in these patients. Since several metabolic pathways are closely tied to T cell and macrophage differentiation, a better understanding of metabolic alterations in immune disorders could help to restore and modulate immune cell functions. This link between energy metabolism and inflammation can be studied employing animal, human or cellular models. Analytical approaches rank from classic immunological studies to integrated analysis of metabolomics, transcriptomics, and proteomics. This review summarizes the main metabolic pathways of the cells involved in the allergic reaction with a focus on T cells and macrophages and describes different models and platforms of analysis used to study the immune system and its relationship with metabolism.

Keywords: -omics; allergy; immune cells; immunometabolism; metabolic regulation.

Figure 1

Phases of allergic inflammation. Example of a simplified allergic asthma model. (A) Early phase reactions, (B) Late phase reactions, (C) Chronic allergic inflammation. AAM, Alternatively activated macrophages; CCL2, Chemokine (C-C motif) ligand 2; FcεRI, High-affinity IgE receptor (Fc epsilon receptor I); GM-CSF, Granulocyte-macrophage colony-stimulating factor; IgE, Immunoglobulin E; IL, Interleukin; ILC2, Type 2 innate lymphoid cell; LTB₄, Leukotriene B4; LTC₄, Leukotriene C4; MC, Mast cell; MMPs, Matrix metalloproteinases; PAF, Platelet-activating factor; PGD₂, Prostaglandin D2; Th2, Type 2 T helper cell; TNF-α, Tumor necrosis factor alpha. Adapted from Galli et al. Nature 2008;454 (7203),445-454. Created with BioRender.com.

Figure 2

Summary of human cellular metabolism. In green steps from the glycolysis pathway, in yellow the PPP, in dark blue nucleic acid biosynthesis, in orange the TCA, in purple fatty acid oxidation and lipogenesis, in light blue amino acid metabolism. Ala, Alanine; Asn, Asparagine; Asp, Aspartate; Cys, Cysteine; Gln, Glutamine; Glu, Glutamate; Gly, Glycine; His, Histidine; Ile, Isoleucine; Leu, Leucine; Lys, Lysine; Met, Methionine; OXPHOS, Oxidative phosphorylation; PEP, Phosphoenol pyruvate; Phe, Phenylalanine; PPP, Pentose phosphate pathway; Pro, Proline; Ser, Serine; TCA, Tricarboxylic acid cycle Thr, Threonine; Trp, Tryptophan; Tyr, Tyrosine; Val, Valine. Created with BioRender.com.

Figure 3

Modulation of antigen presenting cells activity by their metabolism. (A) Modulation of dendritic cells by their metabolism for tolerogenic (blue) and pro-inflammatory (yellow) functions. (B) Modulation of macrophages by their metabolism for M2 (green) or M1 (pink) differentiation. Cer, Ceramide; FA, Fatty acid; HDM, House dust mite; LEP-R, Leptin receptor; MHC, Major histocompatibility complex; oxLDL, Oxidized low density lipoprotein OXPHOS, Oxidative phosphorylation; PUFAs, Poly unsaturated fatty acids; ROS, Reactive oxygen species; SCFAs, Short chain fatty acids; S1P, Sphingosine 1 phosphate; SP1R, Sphingosine 1 phosphate receptor. Created with BioRender.com.

Figure 4

Modulation of CD4 T cells by their metabolism. In green modulation of T effector cells and in purple modulation of T reg cells. HIF 1β, Hypoxia inducible factor 1 β; PD-1, Programmed cell death protein 1; PD1L, Programmed cell death- ligand 1; PEP, Phosphoenol pyruvate; TLR, Toll-like receptor. Created with BioRender.com.