An evolutionary perspective on immunometabolism

Abstract

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.

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

Favorable environments promote investment into 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- and cyto-protective. B. Presence of insults 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 high energy consuming defense arm.

Figure 2.. 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.

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

A. Cells generally utilize aerobic glycolysis and anabolic pathways after receiving growth and differentiation signals in order to grow and proliferate and actively suppress catabolic pathways. Signals that inhibit differentiation and proliferation and promote quiescence generally suppress anabolic pathways and utilize 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 utilize the same pathways as growth and differentiation factors. These signals direct activation of macrophages, dendritic cells and T cells. Anti-inflammatory signals, such as IL10, TGFβ (macrophages) and PD1 (T-cells), inhibit metabolic pathways associated with activation and drive catabolic pathways and FAO. Similarly, signals such as IL4 (macrophages)(107) and IL7 (T-cells) promote corresponding quiescent cellular states (alternatively-activated macrophages and memory T cells, respectively) which also utilize FAO and catabolic pathways.

Figure 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 use 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 confers 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 utilized by the immune system and utilizes corresponding anabolic metabolic programs. Immune tolerance is a dormancy life history program activated by the immune system and utilizes corresponding catabolic metabolic programs.