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. 2022 Mar 9:3:825931.
doi: 10.3389/falgy.2022.825931. eCollection 2022.

Immune Metabolism-An Opportunity to Better Understand Allergic Pathology and Improve Treatment of Allergic Diseases?

Alexandra Goretzki  1 , Jennifer Zimmermann  1 , Yen-Ju Lin  1 , Stefan Schülke  1
Affiliations

Immune Metabolism-An Opportunity to Better Understand Allergic Pathology and Improve Treatment of Allergic Diseases?

Alexandra Goretzki et al. Front Allergy. .
No abstract available

Keywords: Warburg; allergy; immune effector molecules; immune metabolism; metabolic state.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Timeline of pioneering and breakthrough papers that have helped form the field of immune metabolism. The findings are grouped into pioneer studies in the last century, and recent findings about innate immune cells, germinal center (GC) B cells, and T cells. For more detailed information see the main text. LPS, lipopolysaccharide; OxPhos, oxidative phosphorylation; FAO, fatty acid oxidation; GLUT1, glucose transporter 1; HIF-1α, hypoxia-inducible factor 1 alpha; TLR, “Toll” like receptor; ROS, reactive oxygen species; Mφ, macrophage; 4-OI, 4-octyl itaconate; PKM2, pyruvate kinase isozyme M2; EIF2AK2, eukaryotic translation initiation factor 2 alpha kinase 2; TC, T cell; mTOR, mammalian target of rapamycin; PPP, pentose phosphate pathway; AMPK, adenosine monophosphate-activated protein kinase; CaMMK, Ca2+-calmodulin-dependent protein kinase kinase; TCR, T cell receptor.
Figure 2
Figure 2
Metabolic phenotype and the connection to immune cell effector function in activated Antigen Presenting Cells and effector T cells. Antigen Presenting Cells (APCs) activated by e.g., TLR-stimulation switch to a predominant production of energy via glycolysis that drives cytokine production and results in the production and excretion of lactate (Warburg Effect). The switch toward glycolysis is driven by the PI3K/Akt/mTOR-axis. The disrupted Krebs cycle resulting from an undersupply of pyruvate in the mitochondrion is used to (I) generate important immune effector molecules (e.g., itaconate, ROS), (II) fuel post-translational protein modification (e.g., succinylation or acetylation), and (III) free up the mitochondria from energy production in order to promote inflammatory responses via an SDH-, ECSIT- and complex I-dependent production of ROS which in turn drive HIF-1α- and inflammasome-dependent IL-1β production. Activated T cells PI3K/Akt/mTOR-dependently increase their glycolysis but also retain metabolic flexibility with the ability to fuel the mitochondrion with glutamine. Increased glutamine uptake and metabolism is regulated by CD28-dependent ERK-signaling. Moreover, the glycolytic enzyme GAPDH regulated IFN-γ secretion by interacting with IFN-γ mRNA. For more information see text. TLR, “Toll”-like receptor; GLUT1, glucose transporter 1; PDH, pyruvate dehydrogenase; IRG-1, immune-responsive gene 1; IDH, isocitrate dehydrogenase; SDH, succinate dehydrogenase; ROS, reactive oxygen species; HIF-1α, hypoxia inducible factor 1 alpha; SIRT5, Sirtuin 5; ECSIT, evolutionarily conserved signaling intermediate in Toll pathways; MHC, major histocompatibility complex; TCR, T cell receptor; PI3K, phosphoinositide 3-kinase; Akt, protein kinase B; mTOR, mammalian target of rapamycin; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GDH, glutamate dehydrogenase; ERK, extracellular regulated kinase; FAO, fatty acid oxidase.
Figure 3
Figure 3
Immune metabolism in allergies. Immune metabolism in allergic sensitization and pathology (A). Allergens, e.g., derived from house dust mites (HDM), activate epithelial cells and induce a metabolic shift toward glycolysis. Epithelial cells further activate ILC2s and induce FAO-dependent production of the Th2 cytokines IL-5 and IL-13. Some allergens can also bind to TLRs, causing a switch from OxPhos to glycolysis in APCs. Activated ILC2s and APCs further induce the differentiation of naïve T cells into Th2 cells which produce IL-4 in a glycolysis-dependent manner. The activation and differentiation of B cells into IgE-producing plasma cells after IL-4 stimulation is dependent on the Krebs cycle-derived metabolite α-ketoglutarate. The produced IgE binds to the high-affinity FCεRI on mast cells, where cross-linking of IgE leads to a short-term glycolytic phenotype. In contrast, long-term mast cell activation is dependent on OxPhos. Additionally, high concentrations of ROS can directly activate mast cells to release histamine and serotonin. On the other hand, IgE can also bind to basophils, leading to a HIF-1α-dependent activation of glycolysis and subsequent IL-4 production. Immune metabolic changes observed in allergic asthma, rhinitis, dermatitis, and food allergy (B). In allergic asthma, MDSCs have been shown to inhibit allergic asthma by reducing IgE production, immune cell infiltration, and allergen-specific cytokine production. At the same time, high levels of reactive oxygen species (ROS) were found. OxPhos-based anti-inflammatory M2 macrophages may locally inhibit Th2 responses in allergic asthma. Furthermore, for Th2 cells, FAO-dependency could be identified to be essential for survival, while glycolysis was essential for Th2 cytokine production. IL-5 can activate eosinophils, shift their metabolism toward a glycolytic phenotype, and affect their effector functions like autophagy in asthma. Allergic asthma induced by HDM was shown to be TLR4-dependent; while HDM-induced allergic rhinitis was driven by TLR2 activation. In allergic rhinitis, mTOR-deficiency in CD11b+ DCs induced Th17- instead of Th2-biased immune responses. While little is known about immune metabolism in allergic dermatitis and food allergy, they are both connected to a disrupted barrier function of epithelial cells characterized by a predominantly glycolytic phenotype and mitochondrial dysfunction. TLR, “Toll”-like receptor; APC, antigen presenting cell; MC, mast cell; BAS, basophil; ROS, reactive oxygen species; HIF-1α, hypoxia inducible factor 1 alpha; MHC, major histocompatibility complex; mTOR, mammalian target of rapamycin; FAO, fatty acid oxidation; HDM, house dust mite; IgE, Immunoglobulin E; Bϵ, IgE-producing B cell; BC, B cell; TC, T cell; OxPhos, oxidative phosphorylation; MDSC, Myeloid-derived suppressor cell; FcεRI, fragment crystallizable region epsilon receptor I; M2Φ, M2-macrophages; EOS, eosinophils.
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