Available online at www.sciencedirect.com ScienceDirect Induction of innate immune memory: the role of cellular metabolism 1 1,2 Jorge Domı´nguez-Andre´ s , Leo AB Joosten and Mihai G Netea1,3,4 The paradigm that only adaptive immunity can develop providing effective and specific protection against re- immunological memory has recently been challenged by infection by the same microorganism [1]. The para- studies showing that cells from the innate immune system can digm of memory within the adaptive immune system is undergo functional reprogramming, facilitating a faster and essentially the result of somatic genetic re-arrange- enhanced response to secondary infections. This improved ments and clonal selection, while the innate immune secondary response is not always specific, as it can also system is a germline-encoded system that is not capa- protect from infections caused by non-related pathogens. This ble of carrying genetic memory through cell division. has been termed innate immune memory or trained As a result, innate immune system functions were immunity. Trained immunity not only involves rewiring the considered to be only associated with the nonspecific intracellular immune signaling of innate immune cells, but also acute elimination of pathogens either by cellular induces profound changes in cellular metabolic pathways such mechanisms such as phagocytosis, or humoral pro- as glycolysis, oxidative phosphorylation, fatty acid and amino cesses such as the complement system. However, in acid metabolism, increasing the capacity of the innate immune the last years, a series of discoveries have proven that cells to respond to a secondary stimulation. The understanding cells from the innate immune system are also able to of these intracellular processes opens new therapeutic undergo long-term adaptation and acquire enhanced possibilities for the modulation of the innate immune responses capability to respond to certain stimuli, a process that during infections and inflammatory diseases. has been termed innate immune memory or trained immunity [2], which is based on the long-term repro- Addresses gramming that the cells of the innate immune system 1 Department of Internal Medicine and Radboud Center for Infectious such as monocytes, macrophages and NK cells Diseases (RCI), Radboud University Nijmegen Medical Centre, Geert undergo after infection or vaccination [3]. This long- Grooteplein Zuid 8, 6525GA Nijmegen, The Netherlands term innate immune response does not have an anti- 2 Department of Medical Genetics, Iuliu Hatieganu University of Medicine gen-specific character, thus it does not rely on a par- and Pharmacy, 400349 Cluj-Napoca, Romania 3 ticular infectious organism or stimulant (Figure 1). For Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, 53115 Bonn, Germany example, training with b-glucan, a component of fun- 4 Human Genomics Laboratory, Craiova University of Medicine and gal cell walls, induces increased protection against Pharmacy, Craiova, Romania bacterial infections caused by Staphylococcus aureus [4]. Similarly, muramyl dipeptide (MDP), a compo- Corresponding author: Netea, Mihai G ([email protected]) nent of bacterial cell wall peptidoglycan [5], can induce protection against toxoplasmosis, while CpG Current Opinion in Immunology 2019, 56:10–16 dinucleotides provide protection against Escherichia coli This review comes from a themed issue on Innate immunity infections [6]. Edited by Nicolas Manel and James Di Santo Furthermore, a growing body of evidence illustrates that For a complete overview see the Issue and the Editorial the development of trained immunity is not always ben- Available online 19th September 2018 eficial for the organism, and sterile inflammatory insults, https://doi.org/10.1016/j.coi.2018.09.001 such as oxLDL (oxidized low-density lipoprotein) and urate crystals can trigger strong proinflammatory 0952-7915/ã 2018 Elsevier Ltd. All rights reserved. responses that can potentially contribute to development of atherosclerosis or gout [7 ,8]. Increasing evidence links trained immunity to epigenetic and metabolic regulation that involve a number of central cellular metabolic path- ways such as glycolysis, oxidative phosphorylation Introduction (OXPHOS), glutaminolysis, as well as fatty acids and For a long time, it was thought that only adaptive cholesterol-synthesis pathways. In this review we will immunity had the ability to develop immunological focus on the most recent and relevant advances provide memory. Naive B and T lymphocytes first proliferate, novel insights into mechanisms centered on the immu- and then develop antigen-specific, long-lasting mem- nometabolic reprogramming that induces trained immu- ory cells after their first encounter with a pathogen, nity (Table 1). Current Opinion in Immunology 2019, 56:10–16 www.sciencedirect.com Metabolism in trained immunity Domı´nguez-Andre´ s, Joosten and Netea 11 Figure 1 Innate immune memory Adaptive immune memory Metabolic reprogramming Clonal expansion Epigenetic reprogramming Antigen-specificity Enhanced effector functions Generation of long-lasting memory cells Secondary response ‘Trained’ response to antigen Innate immune cells T and B cells Primary response to antigen First response antibody concentration strength of immune response time time First challenge Second challenge Initial exposure Secondary exposure to an antigen to the same antigen Current Opinion in Immunology Immunological memory is not exclusive of T and B lymphocytes. Cells from the innate immune system, such as monocytes, macrophages, DCs and NK cells are also influenced by the contact with different antigens, undergoing metabolic and epigenetic reprogramming and facilitating an enhanced response to future threats. While the responses driven by T and B lymphocytes are antigen-specific, secondary responses involving innate cells can be triggered by a wide variety of stimuli. Metabolic pathways in innate immune that is subsequently released from the cell, instead of memory entering the mitochondria to undergo oxidation [13]. Glycolysis Although less efficient in generating ATP than Aerobic respiration is the main source of ATP in most OXPHOS, glycolysis can be upregulated to a greater human cells. However, glycolysis, an alternative form of extent resulting in a faster production of ATP. As a result glucose metabolism, plays a central role in both immunity of this, innate immune cells can use this metabolic and disease states [9]. Several cell subsets require the adaptation to provide energy and building blocks needed upregulation of glycolysis during immune cell activation: for activation in a timely fashion. activated T cells show increased rates of glycolysis and so do proinflammatory macrophages [10,11], resulting in an Cheng et al. showed that glucose consumption is increased rate of glucose consumption with higher lactate increased in b-glucan-trained macrophages [14]. In a production [12]. After stimulation of macrophages, pyru- follow-up study, Arts et al. proved that glucose was con- vate produced from glucose is transformed into lactate verted into lactate in b-glucan-trained monocytes, vali- dating the upregulation of glycolysis with concomitant Table 1 lactate production in b-glucan-trained monocytes [15 ]. For its part, pro-inflammatory macrophages are highly Overview of pathologies in which a positive or a negative role for innate immune memory mechanisms have been reported glycolytic, but anti-inflammatory macrophages rely mainly on OXPHOS and fatty acid oxidation [16]. High Positive effects mediated by trained immunity-mediated mechanisms rates of glycolytic metabolism and the accumulation of Reversal of immunoparalysis in sepsis patients [44 ,48] intermediate metabolites of the TCA cycle such as fuma- Improved hematopoiesis under chemotherapy treatment [18 ] rate and succinate, control the methylation and acetyla- Non-specific protective effects of vaccinations [19,49] Protection from neonatal sepsis [43 ] tion of histones, forming the metabolic basis for trained immunity [15 ]. Several metabolites from glycolysis and the TCA cycle have been shown to act as cofactors for Negative effects mediated by trained immunity-mediated mechanisms DNA and histone methyltransferases and demethylases as well as histone acetyltransferases and deacetylases [17]. Atherosclerosis and systemic inflammation [32 ,47] Hyper immunoglobulin D syndrome [7 ] After priming of monocytes with b-glucan, genes Diabetes [45] involved in glycolysis, such as those encoding for the Alzheimer disease [46] rate-limiting enzymes of glucose metabolism hexokinase Autoimmune disorders Reviewed in Ref. [50] and pyruvate kinase, were epigenetically upregulated one week later [14]. This metabolic rewiring is also present in www.sciencedirect.com Current Opinion in Immunology 2019, 56:10–16 12 Innate immunity bone marrow progenitors, where b-glucan administration the accessibility to these genes for transcription factors involves a global increase in energy metabolism, being upon secondary stimulation. Acetylation of histones by glycolysis one of the most enriched pathways one week histone acetyl transferases (HATs) requires acetyl-CoA after b-glucan injection in mice [18 ]. Of note, the from the TCA cycle, which is supplied via the export of induction of glycolysis has recently been proven to be mitochondrial citrate [24]. Moreover, it has been shown crucial for the induction trained immunity following BCG that acetyl-CoA derived