Role of Metabolic Reprogramming in Pulmonary Innate Immunity and Its Impact on Lung Diseases

Abstract

Lung innate immunity is the first line of defence against inhaled allergens, pathogens and environmental pollutants. Cellular metabolism plays a key role in innate immunity. Catabolic pathways, including glycolysis and fatty acid oxidation (FAO), are interconnected with biosynthetic and redox pathways. Innate immune cell activation and differentiation trigger extensive metabolic changes that are required to support their function. Pro-inflammatory polarisation of macrophages and activation of dendritic cells, mast cells and neutrophils are associated with increased glycolysis and a shift towards the pentose phosphate pathway and fatty acid synthesis. These changes provide the macromolecules required for proliferation and inflammatory mediator production and reactive oxygen species for anti-microbial effects. Conversely, anti-inflammatory macrophages use primarily FAO and oxidative phosphorylation to ensure efficient energy production and redox balance required for prolonged survival. Deregulation of metabolic reprogramming in lung diseases, such as asthma and chronic obstructive pulmonary disease, may contribute to impaired innate immune cell function. Understanding how innate immune cell metabolism is altered in lung disease may lead to identification of new therapeutic targets. This is important as drugs targeting a number of metabolic pathways are already in clinical development for the treatment of other diseases such as cancer.

Keywords: Asthma; Biosynthesis; Chronic obstructive pulmonary disease; Glycolysis; Mitochondria.

Fig. 1

Overview of catabolic and anabolic metabolism in the cell. Catabolic and anabolic metabolic pathways are interconnected and are coordinated depending on the energy demand and nutrient availability of the cell to ensure adequate supply of energy and macromolecules. In this figure, catabolic pathways are shown in blue boxes and pathways involved in the biosynthesis of macromolecules and redox balance are shown in green. a Glucose is taken up by cells through GLUTs and undergoes phosphorylation by HK to Glucose-6-P, which enters the glycolytic pathway in the cytoplasm to produce pyruvate. Under normal aerobic conditions, most of the pyruvate is converted to acetyl-CoA by PDH in the mitochondrion. A proportion of pyruvate is converted to lactate, by LDH. A number of glycolytic intermediates feed into amino acid and fatty acid biosynthesis. b Glucose-6-P can be directed to the PPP that generates Ribose-5-P, a precursor of nucleotide biosynthesis, and NADPH, which is required for the maintenance of redox balance and fatty acid synthesis. c Acetyl-CoA is also produced by FAO in the mitochondrion, following fatty acid conjugation to carnitine by the enzyme CPT1. d Citrate, produced by the combination of acetyl-CoA and OAA in the mitochondrial matrix, enters the TCA cycle, which generates the reduced intermediates NADH and FADH₂. Citrate can be used in fatty acid biosynthesis through its conversion to acetyl-CoA by ACL. e NADH and FADH₂ produced by the TCA cycle carry electrons (e⁻), which are used in the process of OXPHOS to reduce oxygen, leading to the production of energy in the form of ATP through the phosphorylation of ADP. Partial reduction of oxygen during OXPHOS leads to the production of ROS. f–g Amino acid catabolism also supports energy production and provides biosynthetic precursors. f Glutamine undergoes glutaminolysis to glutamate, which is converted by GLDH into the TCA cycle intermediate α-ketoglutarate. Glutaminolysis also provides glutamate for the synthesis of the antioxidant glutathione and nitrogen for amino acid and nucleotide synthesis. g Arginine is converted to ornithine and urea through the action of the mitochondrial arginase isozyme, ARG2. The enzyme OAT converts ornithine to glutamate, which is then converted to α-ketoglutarate to feed the TCA cycle. Arginine can alternatively be converted to citrulline by induced NO synthase leading to the production of NO. Citrulline is converted back to arginine through the successive actions of the enzymes ASS and ASL. The activation or differentiation of innate immune cells in response to pathogens and inflammatory mediators is associated with changes in the expression and activity of key metabolic enzymes, leading to a shift in the balance between catabolic and anabolic metabolism. These metabolic changes are required to support innate immune function. Increased glycolysis, FAO, OXPHOS, and arginase activity ensure adequate energy production to support prolonged survival, resolution of inflammation and repair in anti-inflammatory cells, such as M2 macrophages. On the other hand, pro-inflammatory macrophages and activated dendritic, mast cells and neutrophils have truncated glycolysis and/or TCA cycle, leading to accumulation of upstream intermediates, which are channelled towards the PPP and anabolic pathways. This results in increased production of proteins, lipids, nucleotides and ROS, which are required for inflammatory mediator production and anti-microbial effects. Abnormal metabolic reprogramming may be a driver of defective innate immune responses in lung diseases, such as asthma and COPD. Fructose-6-P, fructose-6-phosphate; Fructose-1,6-BP, fructose-1,6-biphosphate; G-3-P, glyceraldehyde 3-phosphate; DHAP, dihydroxyacetone phosphate; 1,3BP-Glycerate, 1,3-biphosphoglycerate; 3P-Glycerate, 3-phosphoglycerate; 2P-Glycerate, 2-phosphoglycerate; P-enolpyruvate, phosphoenolpyruvate; SDH, succinate dehydrogenase; IDH, isocitrate dehydrogenase; acetyl-CoA, acetyl-co-enzyme A; LDH, lactate dehydrogenase; CPT1, carnitine palmitoyltransferase 1; GLUT, glucose transporter; PDH, pyruvate dehydrogenase; HK, hexokinase; Glucose-6-P, glucose-6-phosphate; Ribose-5-P, ribose-5-phosphate; OAA, oxaloacetate; NADH, reduced nicotinamide adenine dinucleotide; FADH₂, reduced flavin adenine dinucleotide; FAO, fatty acid oxidation; TCA, tricarboxylic acid; ARG2, arginase 2; PPP, pentose phosphate pathway; NADPH, reduced nicotinamide adenine dinucleotide phosphate; PK, pyruvate kinase; OXPHOS, oxidative phosphorylation; ATP, adeno­sine triphosphate; ADP, adenosine diphosphate; ACL, ATP-citrate lyase; OAT, ornithine aminotransferase; GLDH, glutamate dehydrogenase; ASS, argininosuccinate synthetase; ASL, argininosuccinate lyase; NO, nitric acid; iNOS, induced NO synthase.

Fig. 2

Metabolic changes associated with innate immune responses in lung disease. An overview of the metabolic changes associated with innate immune cell regulation in asthma (a) and COPD (b). a Studies in animal models show that chronic exposure to inhaled allergen leads to mitochondrial dysfunction in the airway epithelium that is accompanied by a reduction in OXPHOS and activation of glycolysis, which supports the production of cytokines and inflammatory cell recruitment. Bronchial epithelial cells from patients with asthma also show increased glycolysis, but at the same time exhibit up-regulation of ARG 2, which acts as a protective mechanism by restoring OXPHOS, reducing glycolysis and inhibiting inflammatory mediator production. Epithelial-derived IL-33 and TSLP induce the maturation and activation of dendritic and ILC2 that orchestrate adaptive immune responses. Upon activation, DCs show a reduction in FAO and OXPHOS and an up-regulation of glycolysis, PPP and FAS to meet the biosynthetic demands of inflammatory mediator production. IL-33-induced ILC2 maturation, on the other hand, is inhibited by PKM2 through a reduction in the expression of the IL-33 receptor, IL1RL1. Moreover, up-regulation of ARG 1 supports allergen-dependent proliferation of ILC2 cells. IgE produced by B cells activates mast cells to release histamine and lipid mediators driving airway inflammation and hyper-responsiveness. Binding of IgE to its receptor triggers inactivation of PKM2, truncating glycolysis and leading to accumulation of upstream intermediates that are channelled to the biosynthesis of lipid mediators released during degranulation. Studies in animal models report a role of FAO in M2 differentiation of macrophages and the development of allergic inflammation; however, other studies show conflicting findings. b Cigarette smoke and other inhaled pollutants are thought to induce ROS-mediated mitochondrial dysfunction and attenuated energy production, due to impaired FAO and TCA, in the epithelium of patients with COPD. These defects may be accompanied by increased glycolysis and ROS production that drive epithelial-mediated inflammatory cell recruitment and lung pathology. Mitochondrial dysfunction in peripheral and alveolar macrophages from patients with COPD has also been associated with mitochondrial ROS production and increased glycolysis, which possibly lead to increased inflammatory mediator production and defective phagocytosis and bactericidal activity. TSLP, thymic stromal lymphopoietin; OXPHOS, oxidative phosphorylation; ARG 1, arginase 1; ARG 2, arginase 2; ILC2, type 2 innate lymphoid cells; DC, dendritic cells; FAO, fatty acid oxidation; PPP, pentose phosphate pathway; FAS, fatty acid synthesis; PKM2, pyruvate kinase isoform M2; ROS, reactive oxygen species; TCA, tricarboxylic acid; COPD, chronic obstructive pulmonary disease.