Metabolic Reprogramming in Immune Response and Tissue Inflammation

Abstract

Innate and adaptive immunity participate in and regulate numerous human diseases. Increasing evidence implies that metabolic reprogramming mediates immune cell functional changes during immune responses. In this review, we present and discuss our current understanding of metabolic regulation in different immune cells and their subsets in response to pathological stimuli. An interactive biochemical and molecular model was established to characterize metabolic reprogramming and their functional implication in anti-inflammatory, immune resolution, and proinflammatory responses. We summarize 2 major features of metabolic reprogramming in inflammatory stages in innate and adaptive immune cells: (1) energy production and biosynthesis reprogramming, including increased glycolysis and decreased oxidative phosphorylation, to secure faster ATP production and biosynthesis for defense response and damage repair and (2) epigenetic reprogramming, including enhanced histone acetylation and suppressed DNA methylation, due to altered accessibility of acetyl/methyl group donor and metabolite-modulated enzymatic activity. Finally, we discuss current strategies of metabolic and epigenetic therapy in cardiovascular disease and recommend cell-specific metabolic and gene-targeted site-specific epigenetic alterations for future therapies.

Keywords: immune response; inflammatory disease; metabolic reprogramming.

Fig. 1.. Metabolic reprogramming in innate and adaptive immune responses.

Innate immunity is characterized by activation of innate immune cells by pathogen/danger associated-molecular pattern (PAMP/DAMP) or metabolite-associated danger signal (MADS) via pattern recognition receptors (PRR) or metabolic sensor (MS) to facilitate the downstream signaling cascade to initiate an immune response. In contrast, adaptive immunity is composed of cell-mediated and humoral-mediated immunity, which are both antigen-specific processes of activating T and B cells involving in several signals (signal 1 antigen recognition, signal 2 immune checkpoint, signal 3 cytokine stimulation, signal 4 MADS recognition). Metabolic reprogramming participates in both innate and adaptive immune response to regulate immune cell functions, which includes up to 2749 metabolic pathways from 3067 different organisms and 477 human metabolic pathways as identified from the MetaCyc database (https://metacyc.org Ver. 23.1). Metabolic reprogramming may be a dynamic process in which glucose, fatty acid and amino acid metabolism are the most described ones, and finally lead to a metabolic optimization in which distinct metabolic signature determines specific inflammatory or anti-inflammatory immune cell subset differentiation. APC indicates antigen-presenting cell; PAMP, pathogen-associated molecular pattern; DAMP, danger-associated molecular pattern; MADS, metabolites-associated danger signal; MS, metabolic sensor; PRR, pattern recognition receptor; *, MetaCyc database (https://metacyc.org, Ver. 23.1),

Fig. 2. Models of metabolic reprogramming in immune response.

A. Metabolic reprogramming in anti- and pro-inflammatory immune response. In response to the stimulation of various danger signals, dynamic balance of pro- and anti- inflammatory metabolic reprograming determines the direction of immune cell responses. In physiological condition or anti-inflammatory response (left panel), immune cells favor oxidative metabolism, including fatty acid oxidation (FAO) and mitochondrial oxidative phosphorylation (OXPHOS), for energy production and homeostasis of metabolic/cellular function. During pro-inflammatory response (right panel), immune cells switch to active glycolysis and biosynthesis (fatty acid and nucleotide synthesis) for quick energy production and regeneration, whereas, FAO and OXPHOS are suppressed. This metabolic reprogramming produces high levels of cytosolic ROS and mitochondrial ROS. Words and arrows in red indicate activate intermediates or process, whereas the blue color depicts the suppressed ones. B. Metabolic switch in innate and adaptive immune cells according to the inflammatory stage. Innate and adaptive immune cells undergo similar metabolic reprogramming in the early inflammatory stage but switch to different metabolic statuses during the memory stage. In general, upon activation, immune cells switch from OXPHOS to glycolysis for quick ATP production. In the memory stage, innate immune cell relies on glycolytic activity, but adaptive immune cell can switch back to more efficient mitochondrial OXPHOS for long-term survival. Biosynthetic and proliferative activities are increased in the activate stage and memory stage in innate immune cell, whereas may be reduced in memory stage in adaptive immune cell. Methylation status is suppressed in the active stage and may maintain as such in the memory stage of innate and adaptive immune cells. Acetylation-mediated epigenetic reprogramming is potentially upregulated due to increased acetyl CoA production and metabolite-modulated enzymatic regulation. Solid lines represent metabolic changes established. Dashed lines represent metabolic changes that remain to be confirmed. PAMP indicates pathogen-associated molecular pattern; DAMP, danger-associated molecular pattern; MADS, metabolite-associated danger signal; G6P, glucose 6-phosphate; R5P, ribose 5-phosphate; PPP, pentose phosphate pathway; NAD, nicotinamide adenine dinucleotide; NADPH, nicotinamide adenine dinucleotide phosphate; ROS, reactive oxygen species; mtROS, mitochondrial ROS; CH, cholesterol; TG, triacylglycerol; FA, fatty acid; FAO, fatty acid oxidation; FAS, fatty acid synthesis; α-KG, alpha-ketoglutarate; TCA cycle, citric acid cycle; OXPHOS, oxidative phosphorylation; SAM, S-adenosylmethionine; SAH, S-adenosylhomocysteine; Met, methione; Hcy, homocysteine.