An evolutionary perspective on immunometabolism

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

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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.

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