An evolutionary perspective on immunometabolism

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Science  11 Jan 2019:
Vol. 363, Issue 6423, eaar3932
DOI: 10.1126/science.aar3932

Metabolism as a driver of immune response

All living organisms need energy and metabolic building blocks to sustain biological processes. Wang et al. review immunometabolism, applying the principles of life history theory. They highlight recent advances showing the reciprocal interactions between systemic metabolism and immunity, as well as how inflammation can alter the functional state of metabolic organs and their central control by the hypothalamus. Such coordinated cross-talk between whole-body and immune cell metabolism is involved in a variety of health and disease states.

Science, this issue p. eaar3932

Structured Abstract


Metabolism can be broadly divided into anabolic, energy-consuming, biosynthetic processes and energy-generating catabolic processes. Different biological functions rely on primarily catabolic or primarily anabolic metabolism. The field of immunometabolism has advanced our understanding of how allocation of metabolic resources (energy and metabolites) supports host defenses. On cellular, tissue, and organismal levels, emerging evidence demonstrates a complex interplay between metabolism and inflammation that must be precisely regulated to support biological functions. It is now well established that inflammatory signals tend to activate anabolic processes necessary to support immune responses. Additionally, macrophages, dendritic cells, and T cells can undergo metabolic reprogramming to support different types of cellular functions and activities; thus, naïve and memory T cells rely on catabolic metabolism, whereas effector T cells and macrophages stimulated through Toll-like receptors engage in glycolysis and anabolic metabolism. In addition, at least some anti-inflammatory signals promote metabolic programs that are not supportive of the inflammatory response. The dysregulation of these processes underlies many modern human diseases such as sepsis, diabetes, and obesity.


We apply evolutionary and ecological principles of life history to discuss the recent advances in immunometabolism within a unifying framework. From this perspective, we highlight the parallels between cellular and systemic control of metabolism. According to life history theory, biological programs can be broadly divided into growth, reproduction, and maintenance. The choice among these programs is dictated by the quality of the environment. Thus, favorable environments promote growth and reproduction, whereas hostile environments promote maintenance and survival programs. These life history programs operate at both organismal and cellular levels. At the organismal level, different hypothalamic-pituitary axes control the engagement of metabolic programs that support organismal growth, reproduction, and maintenance. At the cellular level, activated and quiescent states also broadly correspond to cellular growth and reproduction (proliferation) versus maintenance (quiescence), respectively.

We propose that maintenance programs can be further subdivided into defense and dormancy. This is because the environment can be hostile for two different reasons: It can lack what an organism needs (nutrients and other resources), or it may have what an organism does not want (pathogens, predators, toxins, etc.). Dormancy and defense deal with these two types of hostile environments, respectively. Dormancy (or quiescence) is an energy-preserving state that permits survival in the face of nutrient scarcity. Defenses, on the other hand, are energy-consuming processes that protect from hostile factors, such as pathogens. We then apply these concepts to immunometabolism and highlight important implications for the logic behind the coordination of cellular function with corresponding metabolic programs.


Dysregulation of metabolism and inflammation is a common feature of most of the prevalent modern human diseases. Understanding the complex cellular, tissue, and organismal biology that drive disease pathogenesis is an urgent need. The conceptual framework presented here highlights the logic of metabolic control and the parallels between systemic and cellular metabolism; moreover, it illuminates important areas of exploration in the fields of neuroendocrinology, metabolism, and inflammation biology.

A life history perspective of metabolic programs.

In favorable environmental conditions, growth and reproduction programs are engaged, which rely on anabolic metabolism. Under unfavorable environmental conditions, maintenance programs are engaged. There are two types of maintenance programs: dormancy and defense. Dormancy is induced by nutrient scarcity and relies on energy-preserving catabolic metabolism, whereas defense is induced by infections (and other hostile factors) and requires the support of anabolic metabolism. GH, growth hormone; LH, luteinizing hormone; FSH, follicle-stimulating hormone; SNS, sympathetic nervous system; GC, glucocorticoid.


Metabolism is at the core of all biological functions. Anabolic metabolism uses building blocks that are either derived from nutrients or synthesized de novo to produce the biological infrastructure, whereas catabolic metabolism generates energy to fuel all biological processes. Distinct metabolic programs are required to support different biological functions. Thus, recent studies have revealed how signals regulating cell quiescence, proliferation, and differentiation also induce the appropriate metabolic programs. In particular, a wealth of new studies in the field of immunometabolism has unveiled many examples of the connection among metabolism, cell fate decisions, and organismal physiology. We discuss these findings under a unifying framework derived from the evolutionary and ecological principles of life history theory.

Metabolism is the core process underlying all biological phenomena. All biological processes require energy sources and metabolic building blocks. Metabolism generally falls into (i) anabolic, energy-consuming, biosynthetic pathways or (ii) catabolic, energy-producing pathways. Historically, our knowledge of these core biochemical pathways was primarily gleaned from research of post-mitotic cells. Recent studies of the immune system have demonstrated a dynamic and finely tuned connection between metabolic programs and the specialized cellular functions they support during the course of the immune response. A number of specific regulatory pathways demonstrating the crucial role of metabolism in immunity have been elegantly characterized and have resulted in the emergence of the new field of immunometabolism. Several excellent recent reviews summarize these advances (16) and demonstrate that on the cellular, tissue, and organismal level, there is a critical role for metabolism in controlling immunity and that inflammation, in turn, has a profound impact on metabolism. This reciprocal relationship is fundamental to the immune response and is at the center of a myriad of modern human diseases including obesity, diabetes, sepsis, and autoimmune/autoinflammatory diseases.

At the heart of immunometabolism is the regulated allocation of metabolic resources (energy and building blocks) required to support host defense and survival. Here, we discuss a unifying framework for these complex interactions based on general concepts of life history theory that explains evolutionary patterns of resource allocation in diverse environments.

Life history theory as an organizing principle in biology

Living creatures use different strategies to optimize reproductive success in the face of constraints imposed by the environment. These strategies are specific combinations of so-called “life history traits” such as size at birth, temporal pattern of growth, age and size at reproductive maturity, fertility, and lifespan, which vary vastly among species. For example, krill grow to only a couple of centimeters and lay thousands of eggs per brood, while the blue whales that dine on them can grow to nearly 100 feet and only give birth once every several years. Life history theory aims to explain this tremendous diversity of lifestyles through analysis and modeling of various resource distribution strategies in the context of species-specific sets of environmental challenges (7).

Since its conception in the 1950s, life history theory has clearly demonstrated that in order to maximize reproductive success, organisms must effectively optimize distribution of finite resources into growth, reproduction, and environment-specific survival strategies (maintenance) (7). Traditionally, life history theory has identified growth, reproduction, and maintenance as the three fundamental biological programs into which resources can be invested depending on the quality of the environment. Favorable environmental conditions, including abundance of nutrients, promote investment in the anabolic and energy-consuming processes of growth and reproduction, whereas unfavorable conditions, including nutrient scarcity, require reallocation of available resources into stress-specific catabolic and energy-saving maintenance mechanisms (7).

Two types of maintenance programs: Defense and dormancy

There are two ways in which the environment can be unfavorable: absence of sufficient resources (typically nutrients), or presence of factors with negative impact on fitness (e.g., predators, pathogens, and toxins). Accordingly, maintenance programs induced by these adverse environments are of two types: dormancy and defense, respectively (Fig. 1). Scarcity of resources induces states of dormancy, where non-essential functions, including growth and reproduction, are temporarily suppressed. Dormancy programs promote energy conservation, rely on catabolic metabolism, and are generally associated with high resistance to environmental stressors. At the extremes, these programs can take the form of suspended animation, such as hibernation and dauer. Hibernating mammals, which build up tremendous stores of fat reserves prior to hibernation, drastically decrease their metabolic rate and rely on catabolic programs associated with the metabolism of fatty acids (8). Hibernating mammals have elevated resistance to multiple stressors, including oxidative damage (9), traumatic injury (10), and hypothermia (11). Dormancy programs in lower organisms, such as dauer in Caenorhabditis elegans (12) and extreme abiotic states in tardigrades (13), also show pronounced resilience to environmental stressors. Concordantly, transcriptional analyses of these organisms demonstrate a shift toward catabolic programs and fatty acid metabolism (14, 15).

Fig. 1 Dormancy and defense are distinct programs of maintenance.

Favorable environments promote investment in growth and reproduction. Unfavorable environments are of two types—resource scarcity and presence of insult (pathogen, toxin, etc.)—and both lead to divestment in growth and reproduction. (A) Resource scarcity induces dormancy states, which are characterized by divestment in non-essential functions, energy conservation, and reliance on catabolic metabolism. These programs are generally tissue-protective and cytoprotective. (B) Presence of insult induces defense states, which are characterized by energy consumption and anabolic metabolism. Components of the system that are not required for defense engage dormancy both for protection and to divert resources to the defense arm, which requires high energy consumption.

Like dormancy, defense programs occur at the expense of growth and reproduction, but unlike dormancy, they are energy-consuming and rely on anabolic metabolism to fuel protective responses against pathogens and other hostile environmental factors (Fig. 1B). For example, immune response to pathogens relies on anabolic programs associated with glucose and glutamine utilization, necessary to support leukocyte proliferation and biosynthesis of proteins and other biomolecules involved in defenses (13). Thus, dormancy and defense, although both are part of maintenance, rely on different metabolic programs. Note also that a response to some adverse environments can belong to either dormancy or defense, depending on the animal group. For example, the maintenance program induced by cold temperature could be classified as dormancy in poikilothermic animals, yet be considered as defense in homeothermic animals.

Although life history theory was originally developed as an organizing framework for evolutionary ecology, similar principles can also be applied at the level of organisms and cells. In this context, growth, reproduction, and maintenance can be referred to as life history programs. This view can provide a unifying framework for control and coordination of cellular and organismal metabolism.

The hypothalamus as a central coordinator of organismal life history programs

On the organismal level, the growth, reproduction, and maintenance programs identified in life history theory bear distinct resemblance to the three neuroendocrine pathways known as the hypothalamic-pituitary (HP) axes (Fig. 2). Control of somatic growth is largely governed by the growth hormone–insulin-like growth factor (GH-IGF) axis (16). Growth hormone (GH) is secreted from somatotroph cells in the anterior pituitary gland. The secretion of GH from the anterior pituitary is promoted by growth hormone–releasing hormone (GHRH) produced by neurons in the periventricular nucleus of the hypothalamus. GH acts through the growth hormone receptor on hepatocytes and other cell types to promote secretion of insulin-like growth factor 1 (IGF-1), which acts on multiple tissues to promote anabolic growth programs. Reproduction is regulated by the hypothalamic-pituitary-gonadal (HPG) axis (17). This system begins with hypothalamic neurons in the arcuate nucleus and preoptic area, which secrete gonadotropin-releasing hormone (GnRH). GnRH acts on gonadotrophs in the anterior pituitary gland to induce secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH), which promote a variety of sex-specific reproductive functions, in large part by inducing gonadal secretion of the sex hormones, testosterone and estrogen. Finally, the hypothalamic-pituitary-adrenal (HPA) axis controls glucocorticoid production, which, in addition to sympathetic tone, is a common feature of the response to a variety of environmental stressors (infection, cold, predation, etc.) (18). Neurons in the paraventricular nucleus of the hypothalamus secrete corticotropin-releasing hormone (CRH). CRH induces corticotrophs in the anterior pituitary gland to release adrenocorticotropic hormone (ACTH) into the blood stream. ACTH then acts on the cells in the cortex of the adrenal gland to promote glucocorticoid secretion. Thus, these three hypothalamic-pituitary axes act as central coordinators of organismal life history programs.

Fig. 2 The hypothalamus as a central coordinator of organismal life history programs.

The growth, reproduction, and maintenance arms of life history theory correspond on the organismal level to the growth hormone–insulin-like growth factor (GH-IGF), hypothalamic-pituitary-gonadal (HPG), and hypothalamic-pituitary-adrenal (HPA) axes, respectively. These axes all initiate at the level of the hypothalamus and can be engaged or disengaged, depending on inputs reporting on the quality of the environment. The GH-IGF axis regulates hepatic secretion of IGF-1, which is known to be essential to growth. The HPG axis controls the gonadal secretion of sex hormones, which are necessary for reproductive maturation and function. The HPA axis governs adrenal secretion of glucocorticoids, which are a common component of responses to environmental stress.

Life history programs on an organismal level are coupled to specific metabolic programs. The GH-IGF axis ultimately results in secretion of IGF-1, which has been shown to promote anabolic metabolism, growth, and storage of excess energy (19). Similarly, sex hormones have well-known anabolic effects, which can facilitate energy storage in various ways, such as increased muscle and adipose mass (20). In contrast, the effect of glucocorticoids on tissues is primarily catabolic (21, 22). Thus, the physiological effects of the three hypothalamic-pituitary axes correspond to the three life history programs (growth, reproduction, and maintenance), with growth and reproduction being anabolic and maintenance being catabolic.

Because all three of these axes are initiated at the level of the hypothalamus, the hypothalamus can be thought of as the sensor of environmental quality that then directs engagement of appropriate organismal life history programs. Evidence for hypothalamic sensing of environmental quality is abundant. The medial basolateral hypothalamus is particularly well positioned for direct sensory function because it is not protected by the blood-brain barrier, allowing it to access and evaluate the contents of the blood (23). Neurons in this anatomic area, including neuropeptide Y/agouti-related protein (NPY/AgRP) and pro-opiomelanocortin (POMC) neurons, can sense nutritional status, either directly (24, 25) or through the effects of insulin and leptin (26). The hypothalamus has also been shown to sense other environmental conditions, including hot (27) and cold (28) temperature, thirst (29, 30), and infection (31, 32).

There is strong evidence that hypothalamic sensing of a hostile environment can lead to direct suppression of the GH-IGF and HPG axes at the hypothalamic level. Following the example of NPY/AgRP and POMC neurons above, α-melanocyte stimulating hormone secreted by POMC neurons (in response to nutrient abundance) has been shown to activate a large fraction of GnRH neurons, whereas NPY, which can be secreted by NPY/AgRP neurons (in response to nutrient scarcity), has been shown to suppress GnRH neurons (33). NPY/AgRP neurons have also been shown to inhibit Kiss1-expressing neurons (34), which are critical drivers of reproductive maturation and function. AgRP neuron activation may also lead to suppression of the GH–IGF-1 axis (35). Finally, CRH can directly suppress GnRH secretion as well as GHRH-induced GH secretion (36). Taken together, these examples illustrate how the hypothalamus controls the choice of life history programs as a function of the quality of the environment and orchestrates the suppression of growth and reproductive functions while engaging maintenance programs in unfavorable environments.

Cellular life history programs

At the cellular level, life history programs of cell growth, reproduction (proliferation), and maintenance are reflected in the organization of cell signaling pathways. Engagement of the cellular equivalents of life history programs is dictated by sensing of local cellular environment (nutrient and oxygen availability and various stress factors) and global organismal state (which in turn reflects the organismal environment).

Cells receive information about the organismal environment via various endocrine signals, including signals for growth (GH, IGF-1, and other growth factors), reproduction (estrogen and androgen), and maintenance (glucocorticoids), as well as endocrine hormones which communicate systemic status, such as those permissive for growth and reproduction (i.e., insulin and leptin) or maintenance [i.e., glucagon, ghrelin, fibroblast growth factor (FGF) 21, and inflammatory cytokines]. Interestingly, GH has a dual role in controlling organismal life history programs: In addition to being involved in the GH–IGF-1 axis that controls growth and anabolic metabolism, GH is induced by ghrelin during fasting and promotes lipolysis and gluconeogenesis to enable adaptation to starvation (37, 38). Which of the two opposing pathways is induced by GH is likely dictated by the metabolic status of the organism, such that GH promotes IGF-1–mediated anabolic growth programs in fed states, whereas GH promotes catabolic maintenance programs in fasted states. The details of how these effects of GH are regulated remain to be established.

The local cellular environment is sensed by various nutrient sensors, including adenosine 5′-monophosphate–activated protein kinase (AMPK), which senses adenosine triphosphate; carbohydrate response element–binding protein (ChREBP), which senses glucose; general control nonderepressible 2 (GCN2) and mechanistic target of rapamycin (mTOR), which sense amino acids; sterol regulatory element–binding protein 2 (SREBP-2), which senses sterols; and peroxisome proliferator–activated receptor α (PPARα) and PPARγ, which sense fatty acids (39, 40). Oxygen level is sensed by hypoxia-inducible factor 1 and 2 (HIF-1/2)–prolyl hydroxylase (PHD) sensors (41). In addition to nutrient and oxygen availability, cells sense the local presence of various negative microenvironmental factors, including pathogens [Toll-like receptors (TLRs), retinoic acid inducible gene I (RIG-I), melanoma differentiation-associated protein 5 (MDA-5)], oxidative stress [nuclear factor erythroid 2 related factor 2 (NRF-2)], DNA damage (p53), deviations in pH (G-coupled protein receptors GPR132, GPR4, GPR68, and GPR65), heavy metals [metal regulatory transcription factor I (MTF-1)], and protein damage [X-box binding protein I (XBP-1) and heat shock factor I (HSF-1)] (42). Activation of these pathways is generally known as the cellular stress response.

Cells engage in their own version of life history programs in reaction to the local environmental and organismal state: When the environment is sensed as favorable, cells grow, proliferate, and engage specific signaling pathways and transcriptional programs that execute these cellular functions. When the environment is sensed as unfavorable, cells engage defense or dormancy programs orchestrated by the corresponding signaling and transcriptional programs (Table 1). The functions of p53 provide a particularly well-studied example illustrating the regulation of cellular life history programs: In response to sensing an adverse cellular state (DNA damage and other stressors), p53 suppresses growth factor signaling and anabolic metabolism required to support cell proliferation, while promoting catabolic metabolism, autophagy, and dormancy (43).

Table 1 Cellular life history programs and their associated signaling and transcriptional programs.

ER, estrogen receptor; AR, androgen receptor; RIP140, receptor interacting protein 140; Gαi and Gαs, Gs and Gi α subunits; ATF4, activating transcription factor 4; GSK3b, glycogen synthase kinase 3β; GR, glucocorticoid receptor; PGC-1α, peroxoisome proliferator-activated receptor γ coactivator 1-α; ERRα, estrogen-related receptor α; cAMP, cyclic adenosine monophosphate; CREB, cAMP response element–binding protein.

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Cellular detection of nutrient scarcity leads to activation of catabolic processes characterized by engagement of AMPK, FOXO1/FOXO3a, fatty acid oxidation, and autophagy pathways (44). Additionally, these programs repress the anabolic processes of cellular growth and proliferation programs through suppression of the phosphatidylinositol 3-kinase (PI3K)–protein kinase B (AKT) and mTOR pathways (4547). A fundamental aspect of a cell’s life history program choice is between quiescence (and self-renewal in stem/progenitor cells) and proliferation and differentiation. Stem/progenitor cell quiescence and self-renewal are promoted by resource scarcity and are controlled by the same pathways that control dormancy—AMPK, FoxO, STAT3 (signal transducer and activator of transcription 3), and SMADs—whereas proliferation and differentiation are promoted by PI3K-AKT, mTOR, and other regulators of anabolic metabolism (4). Interestingly, asymmetric cell division of stem cells results in unequal partitioning of these signaling components between self-renewing and differentiating daughter cells (4851), reflecting the fundamental role these pathways play in cell fate decisions along life history programs. Quiescence/dormancy and self-renewal rely on catabolic metabolism, including oxidative phosphorylation (OxPhos), whereas cell activation, proliferation, and differentiation require glucose and glutamine, aerobic glycolysis, and anabolic metabolism. This is clearly seen in the well-studied examples of T cell metabolism, where naïve and memory T cells (self-renewing/quiescent states) rely on OxPhos, whereas activated/effector T cells rely on aerobic glycolysis and require activation of PI3K-AKT and mTOR pathways (1).

Thus, when viewing metabolic reprogramming from a cellular life history perspective, it is clear that the same signaling pathways and transcriptional programs that enable specific cellular functions such as proliferation also engage specific metabolic programs to support these functions. Growth, proliferation, and other resource-utilizing processes are supported by anabolic metabolism, whereas maintenance relies on either catabolic (dormancy) or anabolic (defense) metabolic programs, as we discuss next (Fig. 3A).

Fig. 3 Cellular life history programs and their corresponding metabolic programs.

(A) Cells generally use aerobic glycolysis and anabolic pathways after receiving growth and differentiation signals in order to grow, proliferate, and actively suppress catabolic pathways. Signals that inhibit differentiation and proliferation and promote quiescence generally suppress anabolic pathways and use catabolic pathways associated with fatty acid oxidation (FAO) and oxidative phosphorylation (OxPhos). (B) Inflammatory and immunostimulatory signals (e.g., TCR, CD28, Toll-like receptors) are mitogenic signals for immune cells and use the same pathways as growth and differentiation factors. These signals direct the activation of macrophages, dendritic cells, and T cells. Anti-inflammatory signals such as IL-10, TGF-β (macrophages), and PD1 (T cells) inhibit metabolic pathways associated with activation and drive catabolic pathways and FAO. Similarly, signals such as IL-4 (macrophages) (107) and IL-7 (T cells) promote corresponding quiescent cellular states (alternatively activated macrophages and memory T cells, respectively), which also use FAO and catabolic pathways. MAPK, mitogen-activated protein kinase; LIF, leukemia inhibitory factor; BMPs, bone morphogenetic proteins.

Dealing with infection: Immune resistance (defense) and tolerance (dormancy)

For an organism to survive infection, it must reduce the microbial burden (through immune resistance mechanisms) and tolerate the damage caused by infection (through various tissue-protective and survival mechanisms unrelated to pathogen control) (52, 53). Immune resistance requires the proliferation of immune cells and generation of lipid and protein mediators that direct the immune response. These rely on the same energy-consuming anabolic pathways as growth and proliferation induced by growth factors. Thus, the immune response corresponds to the defense component of maintenance programs (Fig. 3B). On the other hand, at least some tolerance mechanisms, which confer stress resistance and tissue protection from inflammatory and pathogen-induced damage, may largely rely on catabolic metabolism and correspond to the dormancy component of maintenance programs. Indeed, as noted earlier, dormancy programs rely on catabolic metabolism and confer stress resistance. We further propose that these dormancy programs are likely induced by specialized signals (including adenosine, ketone bodies, FGF21, and glucocorticoids) that coordinate organ-specific switches to tissue-protective, dormant metabolic states.

Immune resistance (defense)

It is now well established that for immune cells to execute their specialized functions during an infection, they must engage anabolic metabolism. Under homeostatic conditions (in the absence of infection), macrophages maintain homeostatic proliferation in the presence of mitogens (growth and proliferation) in a c-Myc–dependent fashion, but upon activation with lipopolysaccharide (LPS) they actively suppress c-Myc expression and switch to a mTOR-HIF1α–dependent metabolic program (54). This example illustrates that although both growth/proliferation and defense rely on anabolic programs, they have distinct features and are controlled by different signaling and transcriptional programs (in this example, c-Myc versus HIF1α). In addition to activating anabolic metabolism, TLR signals induced by LPS in macrophages actively suppresses catabolic programs. LPS stimulation leads to inhibition of AMPK (a key activator of catabolic metabolism) (55) and up-regulation of inducible nitric oxide synthase (iNOS) and NO production, which nitrosylates proteins in the mitochondrial electron transport chain, leading to suppression of OxPhos (56, 57). In contrast, the inflammatory functions of macrophages are dependent on aerobic glycolysis and anabolic programs. Upon stimulation by LPS, macrophages activate mTOR (58) while increasing phosphofructokinase 2 (μ-PFK2) and thus enhancing aerobic glycolysis (59). In a coordinated fashion, LPS activates mTOR-HIF1α pathways, leading to increased transcription of glucose transporter 1 (GLUT1) (60) to fuel aerobic glycolysis. The production of interleukin (IL)–1β also requires the activation of mTOR-HIF1α (61, 62) as well as fatty acid synthase (63) and the suppression of AMPK and autophagy (64, 65). AMPK suppression in macrophages has also been shown to be critical for maximal induction of tumor necrosis factor (TNF), IL-6, and eicosanoids (66). In all cases, limiting glucose or interfering with the subsequent anabolic pathways ablates macrophage inflammatory responses (5962).

Dendritic cells (DCs) also switch to aerobic glycolysis upon activation and actively suppress OxPhos through the actions of NO and mTOR-HIF1α (67). mTOR-HIF1α has been shown to be required for up-regulation of the costimulatory molecules CD80 and CD86 (68) as well as the production of cytokines (69). Thus, dendritic cell functions are also coupled with supportive anabolic metabolic programs.

Aerobic glycolysis in activated T cells generates the supply of substrates used for growth and proliferation and regulates the efficient production of effector cytokines critical for the immune response (3, 70). Unlike macrophages and DCs, T cell activation initiated by T cell receptor (TCR)/CD28 also augments OxPhos to support rapid increase in energy demand (71, 72). It was recently shown that subsequent to TCR engagement, the mitochondrial proteome is remodeled to promote one-carbon metabolism (73). Ablation of serine hydroxymethyltransferase 2 (SHMT2), the first enzyme in this pathway, impairs CD4 T cell survival and proliferation (74). Consistent with this finding is the observation that unequal elimination of mitochondria in daughter cells after TCR activation leads to different functional outcomes (48, 75). Maintenance of mitochondria has been linked to anabolic metabolism and enhanced glycolysis via PI3K and mTOR pathways and suppression of AMPK and autophagy, whereas mitochondrial clearance has been linked to a catabolic program activated by FOXO1 (75). This process was shown to be critical for control of differentiation (defense, PI3K, mTOR) versus self-renewal (dormancy, FOXO1) (75). Consistent with these findings, one general feature of long-lived memory T cells is their dependence on OxPhos metabolism and fatty acid utilization as well as active suppression of glycolysis and glucose utilization (70, 76).

Given that immune cell activation requires anabolic metabolism, one way that anti-inflammatory signals can operate is by suppressing nutrient acquisition and anabolic programs in immune cells. Indeed, IL-10 negatively regulates macrophage inflammatory response by suppressing GLUT1 cell surface expression, glycolytic flux, and mTOR activity while simultaneously promoting OxPhos and mitophagy, which negatively regulate macrophage activation (64). Transforming growth factor–β (TGF-β) was also recently shown to negatively regulate macrophages by interfering with mitochondrial dynamics (77). In T cells, engagement of the inhibitory receptor PD1 (programmed cell death protein 1) leads to inhibition of glycolysis and promotion of fatty acid oxidation (78, 79). Taken together, these examples suggest that one major mode of action of anti-inflammatory and immune-suppressive signals might be through the suppression of anabolic metabolic programs required for activation of immune and inflammatory responses (Fig. 3B).

Disease tolerance (dormancy)

Surviving an infection requires both pathogen clearance (resistance to infection) and tissue protection from pathogens and inflammatory damage (tolerance to infection). Although immune resistance relies on anabolic metabolism, we propose that some (but not all) aspects of tolerance may primarily be based on catabolic dormancy programs. Indeed, the inflammatory response activates many components of dormancy programs typically induced by nutrient scarcity (Fig. 4A).

Fig. 4 Inflammation engages both defense and dormancy programs.

Dormancy programs are induced by resource scarcity. Resource scarcity is sensed by the hypothalamus and endocrine organs, which then send signals that activate catabolic cellular and organismal programs associated with quiescence and stress resistance. Defense programs are induced by environmental insults such as infectious agents. These are sensed by the immune system, which then uses inflammatory mediators to activate anabolic cellular and organismal programs associated with proliferation and biogenesis. (A) During the inflammatory response to infection, inflammatory mediators engage dormancy-associated programs. While the immune system is engaged in defense programs, other parts of the organism are engaged in dormancy programs, which confer stress resilience and tissue protection. (B) The host response to infection is divided into immune resistance and immune tolerance. Immune resistance is a defense life history program used by the immune system, whereas immune tolerance is a dormancy life history program activated by the immune system; they use corresponding anabolic and catabolic metabolic programs, respectively.

A prominent component of acute inflammation illustrating this point is sickness behaviors, which include anorexia, loss of libido, social withdrawal, fatigue, and somnolence (80). Sickness behaviors are thought to have a protective role during an infection, although there is limited understanding of the mechanistic basis for this notion. However, sickness behaviors can be seen from the perspective of life history programs as organismal states associated with dormancy and organ protection. All sickness behaviors appear to be induced through the effects of inflammatory mediators, especially prostaglandins, on the corresponding areas of the hypothalamus (81, 82). Thus, sickness behaviors can be thought of as behavioral manifestations of divestment in growth and reproduction (anorexia and loss of libido) and entry into dormancy (hypersomnia, fatigue, malaise, social withdrawal). Consistent with this, under inflammatory challenges, the HPA axis (for maintenance/catabolic programs) is engaged while the HPG and IGF-1 pathways (growth and reproduction/anabolic programs) are suppressed (83, 84). Inflammatory mediators such as TNF, IL-6, IL-1β, type I interferon, and prostaglandins have all independently been shown to directly induce anorexia (82, 85, 86). In addition to the catabolic state induced by activation of the HPA axis, TNF directly liberates free fatty acids through lipolysis (87) while simultaneously reducing glucose utilization in skeletal muscle and adipose tissue, both by decreasing insulin secretion by pancreatic β cells and by inducing insulin resistance in these organs (88, 89). Leptin resistance has also been demonstrated in a variety of inflammatory contexts (90). Furthermore, inflammation and inflammation-induced anorexia induce a modified version of a fasted metabolic state, which is characterized by lipolysis and the liberation of free fatty acids from adipose tissue as well as PPARα-regulated synthesis and secretion of ketone bodies and FGF21 by the liver (91). Moreover, both fasting and infection-induced IL-6 induce hepatic triglyceride secretion (92). Plasma angiopoietin-like 4 (Angptl4) levels also rise during inflammation, which inhibits lipoprotein lipase activity in adipose tissue, such that the increased triglycerides in circulation are readily available for utilization rather than taken up for storage (93). The ability to produce glucocorticoids, liberate alternative fuels through lipolysis, stimulate triglyceride secretion, perform ketogenesis, and induce FGF21 have all been shown to be necessary for surviving inflammatory conditions (91, 94, 95). Conversely, agonism of PPARα and FGF21 pathways has been shown to improve survival (96, 97).

It is becoming increasingly clear that a shift to dormancy-associated metabolic programs in vital organs during an immune response confers tissue protection. For example, alternative fuels such as ketone bodies have been shown to have direct cytoprotective effects, primarily by reducing oxidative damage (98, 99) but also by directly signaling to negatively regulate inflammation, as in the cases of the β-hydroxybutyrate receptor Gpr109a (100, 101) and the effect of ketone bodies on the NLRP3 (nucleotide-binding oligomerization domain-like receptor family pyrin domain containing 3) inflammasome (102). On the cellular level, upon oxidative stress, hematopoietic stem cells shift metabolic programs to OxPhos and fatty acid metabolism in a cytochrome c oxidase 2–dependent fashion, which improves their survival (103). Indeed, engagement of catabolic/maintenance programs has been observed to confer stress resistance in a variety of settings, such as in the beneficial tissue-protective effects seen in calorie restriction (104), ischemic preconditioning (105), and therapeutic hypothermia (106).

In summary, the inflammatory response to infection (a maintenance program) suppresses growth and reproduction and is a composite of resistance (defense component of maintenance), which relies on anabolic programs and promotes pathogen clearance, and tolerance (dormancy component of maintenance), which relies on catabolic programs and promotes tissue protection (Fig. 4B). Finally, it should be noted that although dormancy is perhaps the most universal mechanism of tolerance, there are many other processes that can promote survival, depending on what is the limiting factor in a given context. For example, tissue repair is an anabolic process (and thus fits better with the definition of defense), but it can clearly contribute to tolerance. Dormancy, on the other hand, can make tissues less susceptible to damage in the first place.


When the life history theory–derived framework is applied in the context of the immune response, it becomes clear why metabolic reprogramming on both the cellular and organismal level is a critical aspect of the host response to infection. On the cellular level, activated immune cells largely require glucose to mount a robust response. This is consistent with the anabolic processes that immune cell activation entails, including rapid proliferation and synthesis of cytokines, antimicrobial proteins, and lipid mediators. Simultaneously, tissues not directly involved in the immune response engage catabolic metabolism and switch fuel usage from glucose to fatty acids and ketones, which support tissue-protective pathways, as dormancy programs are generally highly resistant to stress.

Life history programs encapsulate the fundamental processes of life. Species, organisms, and cells must all grow and reproduce, proliferate, or survive dynamic environments with a limited pool of resources. Proper allocation of these resources (metabolic programming) is necessary to achieve these basic processes of life. Metabolic and inflammatory disorders, such as diabetes, obesity, sepsis, and autoimmune and autoinflammatory diseases, are increasing at alarming rates, with little progress made toward mitigating mortality and morbidity despite substantial technological advancements. The evolutionary perspective on immunity and metabolism may provide a useful framework within which to understand the biology underlying these diseases.

References and Notes

Acknowledgments: We thank members of the R.M. lab for helpful discussion. Funding: Supported by the HHMI, Else Kröner Fresenius Foundation, and the Blavatnik Family Foundation (R.M.); NIH grant K08 AI128745 (A.W.); and NIH grant T32 AI007019 and the Gruber Science Fellowship (H.H.L.). Author contributions: A.W., H.H.L., and R.M. wrote the manuscript and generated the accompanying figures. Competing interests: The authors declare no competing interests.
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