Mini review The interplay between central metabolism and innate immune responses Shih-Chin Cheng, Leo A.B. Joosten, Mihai G. Netea * Department of Internal Medicine, Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands 1. Introduction Cellular metabolism is a complex and delicate process that is regulated by different environmental cues, acting at the level of multiple layers of biochemical regulation. The importance of the central metabolism has been mostly appreciated from its role to maintain homeostasis and bioenergetics balance of an individual. However, recent evidence argues for an important cross-talk between immune system and metabolic regulation, bringing into the spotlight an unexpected layer of metabolic regulation of immune responses. In this review we will integrate the recent literature to present a systematic picture on the mechanisms through which central metabolism regulates the innate immune responses to the intruding pathogens. Once a pathogenic microorganism breaches through the skin or mucosal barriers, it is immediately sensed by the innate immune cells such as Langerhans cell (dendritic cell) or tissue macrophages through germ-line encoded pattern recognition receptors (PRRs) including Toll-like receptors (TLRs), C-type lectin receptors (CLRs), NOD-like receptors (NLSs) or RigI-helicases. Subsequently, the activation of PRRs leads to either immediate phagocytosis of the pathogens or the secretion of soluble mediators such as pro- inflammatory cytokines or chemokines for the further recruitment of the effector cells to the site of infection. During this activation process, the metabolic state of innate immune cells has to switch rapidly in order to meet the heightened energy need from the basal resting state to a hyper active stage. In the basal resting state, the cells use mainly the oxidative phosphorylation (OXPHOS) to generate ATP, process that takes place in the mitochondria through tricarboxylic acid cycle (TCA cycle) as the energy source, and accompanied by consumption of oxygen. However, upon immune activation the central metabolism shifts from OXPHOS to aerobic glycolysis to generate cellular ATP. Although glycolysis produces less ATP per glucose molecule compare to TCA cycle (2 versus 32 ATPs), less enzymatic steps are involved that can be easier enhanced, and therefore more ATP could be produced in a short time as compared to OXPHOS. This switch to aerobic glycolysis is called ‘Warburg effect’, after the first description of this process by Otto Warburg as a characteristic of cancer cell metabolism [1]. However, recent studies have demonstrated that the aerobic glycolysis is an important feature of the active immune metabolic signatures as well. 2. Metabolic shifts in innate immune cells after pathogen recognition 2.1. Oxidative phosphorylation Oxidative phosphorylation (OXPHOS) takes place in the mitochondria and generates ATP through the electron transport Cytokine & Growth Factor Reviews xxx (2014) xxx–xxx * Corresponding author at: Department of Medicine (463), Radboud University Medical Centre, Geert Grooteplein Zuid 8, 6525 GA Nijmegen, The Netherlands. Tel.: +31 24 3618819; fax: +31 24 3541734. E-mail address: mihai.netea@radboudumc.nl (M.G. Netea). A R T I C L E I N F O Article history: Available online xxx Keywords: Immunometabolism Cytokines Glycolysis Oxidative phosphorylation Innate immunity A B S T R A C T A growing body of recent studies bring into light an important cross-talk between immune response and metabolism not only at the level of the organism as a whole, but also at the level of the individual cells. Cellular bioenergetics functions not only as a power plant to fuel up the cells, but the intermediate metabolites are shown to play an important role to modulate cellular responses. It is especially the pathways through which a cell metabolizes glucose that have been recently shown to influence both innate and adaptive immune responses, with oxidative phosphorylation used by resting or tolerant cells, while aerobic glycolysis (also termed ‘Warburg effect’) fueling activated cells. In this review we will address how the center metabolism shifts upon activation in the innate immune cells and how the intermediate metabolites modulate the function of immune cells. ß 2014 Elsevier Ltd. All rights reserved. G Model CGFR-801; No. of Pages 7 Please cite this article in press as: Cheng S-C, et al. The interplay between central metabolism and innate immune responses. Cytokine Growth Factor Rev (2014), http://dx.doi.org/10.1016/j.cytogfr.2014.06.008 Contents lists available at ScienceDirect Cytokine & Growth Factor Reviews jo ur n al ho mep ag e: www .elsevier .c om /loc ate/c yto g fr http://dx.doi.org/10.1016/j.cytogfr.2014.06.008 1359-6101/ß 2014 Elsevier Ltd. All rights reserved.