Metabolic mediators: How immunometabolism directs the immune response to infection

Summary

Here we announce the first part of an exciting new series of reviews exploring the impact of immunometabolism in the interaction between host and pathogen, and in the outcome of infection. This collection discusses the links between metabolism and epigenetic control of cell function, post‐translation modifications of host proteins that determine protein fate and host cell function, the metabolic determinants of cell migration and immune cell activity, and the tussle for iron as a metabolic mediator of host‐pathogen domination. Together these reviews provide engaging new insight into the metabolic signals that guide the dynamic conversation between microbial pathogens and the mammalian hosts they aim to occupy.

The immune system in action is an impressive piece of choreography. Exquisite balance is essential, maintaining protection against a diverse array of pathogens while preventing immune‐mediated pathologies. Understanding the mechanisms behind such balance is a high priority for research and clinical communities. In the last decade, there has been growing interest in immune cell nutrition and metabolism, giving rise to the emerging field of ‘immunometabolism’ and casting new light on the regulation of immune cell activity. Here, we present an exciting new series of review articles that consider immunometabolism in the context of infection, discussing new insights into immune cell migration, function and persistence, and new perspectives on how metabolites can mediate the fraught dialogue between invading pathogens and their host.

The field of immunometabolism rests upon the foundation that immune cells show distinct states of nutrient and energy metabolism during activation compared with their inactivated state. ¹ Superficially, it may be no surprise that an activated cell consumes and uses energy differently than a cell at rest. Nevertheless, this simple premise has resulted in an explosion of inquiry into how nutrient usage and cellular energetics are regulated during an immune response, and how these processes direct downstream cellular function. ² , ³ The study of immunometabolism has been revolutionary in immunology, opening another ‘lens’ through which to view the nuanced complexity of immune response regulation.

Early studies in immunometabolism focused on the gross characterization of shifts in cellular metabolism that occur during immune cell activation. ⁴ , ⁵ In most contexts, both myeloid and lymphoid cells upregulate their consumption of glucose to fuel their effector functions. ⁶ , ⁷ However, immune cell activation is not a simple ‘on/off’ metabolic switch, but rather a qualitative engagement and prioritization of distinct metabolic pathways that can specifically support unique effector outcomes, such as polarization of T helper cells or specification of macrophage effector responses. This review series highlights recent advances in understanding the links between metabolism and function in immune cells, using the context of microbial infection to illuminate immunometabolism in action. The series illustrates the convergence of metabolism with other forms of cellular regulation, including epigenetics, post‐translational modifications and nutrient competition. The reviews emphasize the role of immunometabolism in the beauty of the immune orchestration required to eradicate pathogens and yet maintain balance throughout the immune responses to infection.

We are publishing the review series in two parts. The first half of this series, presented here, focuses on metabolic mechanisms and discusses their influence on immune cell activity and protection from infection. Topics in this part of the series include the influence of cellular metabolism on epigenetic regulation, post‐translational protein modification, immune cell trafficking and intestinal homeostasis. The second half of the series, which will be published in early 2021, provides specific examples of immunometabolism in action in particular infections, illustrating its ability to mediate the conversations between host and pathogen and to influence disease outcome.

In the first article of this series, Lio and Huang address emerging evidence of the connection between metabolic processes and epigenetic regulation of gene expression. ⁸ The authors introduce one‐carbon metabolism and highlight the key metabolites S‐adenosylmethionine (SAM) and α‐ketoglutarate (αKG) as important contributors to the DNA methylation cycle in both innate and adaptive immune cells. They discuss the critical role of the TCA cycle intermediate αKG as a cofactor for a family of dioxygenase enzymes, which play fundamental roles in the epigenetic regulation of inflammation‐associated genes. ⁹ These dioxygenases include the ten‐eleven translocation (TET) methylcytosine oxidases, which are required for proper lymphocyte development and activation, neatly illustrating the importance of metabolic regulation of gene expression.

TET methylcytosine oxidases are also iron‐dependent, ⁹ , ¹⁰ and Geros and colleagues discuss the central importance of iron as a metabolic regulator of both host and pathogen. Iron is essential to every living cell, being a required cofactor for enzymes involved in DNA synthesis and mitochondrial function. Tight regulation of iron availability is a key immune defence against bacterial pathogens, and the human gut is a dynamic front line of a battle for access to iron. Host defence mechanisms that capture iron and prevent accessibility to microbes affect the intestinal microbiota and unwanted pathogens, and Geros et al highlight the metabolic dialogues between host, pathogen and commensal that determine health and dysbiosis. The authors also provide valuable perspectives on the therapeutic potential of targeting iron metabolism and iron availability, considering the impact on both host and pathogen.

Building on the conversation between host and pathogen, Quik, Hokke and Everts introduce us to a novel mechanism of metabolic control over immune defences. ¹¹ They describe an emerging connection between the hexosamine biosynthesis pathway (HBP) and a specific form of post‐translational glycosylation termed O‐GlcNAcylation. O‐GlcNAcylation can alter functional properties of the proteins that it modifies, ¹² , ¹³ and the pathway particularly targets transcription factors and epigenetic regulators. This review dovetails beautifully with the work presented by Lio and Huang, both describing the multifaceted ways in which cellular metabolism can influence genetic regulation. Quik and colleagues comprehensively address the existing evidence for HBP‐mediated O‐GlcNAcylation in regulating immune cell function in responses to bacterial, viral, fungal and parasitic infections, providing exciting new insight into metabolic control across the broad diversity of antimicrobial responses. Their work highlights the therapeutic promise of targeting HBP metabolism and O‐GlcNAcylation as a mechanism of host‐protective immunological intervention.

Our final mechanistic article is a thought‐provoking piece by Guak and Krawczyk, in which the authors consider how shifts in nutrient usage and energy production support the motility and location of both innate and adaptive immune cells. ¹⁴ One of the highlights of this article is in its discussion of the exciting finding that metabolic enzyme activity and energy production can be geospatially compartmentalized within the cell to support the unique energetic demands of directional chemotaxis. ¹⁵ This pertains not only to the compartmentalization of glycolytic enzyme machinery in the cytoplasm, but also to the specific regional location of mitochondria in areas of the cell that support high‐energy demands, such as the leading edge of a migrating cell. Guak and Krawczyk discuss nuanced metabolic contexts such as hypoxia and dyslipidaemia, and describe the impact of these pathophysiological states on cellular metabolism and consequently cell motility. Such metabolic restrictions are decisive components of pathological microenvironments, and understanding their significance is an essential step towards therapeutic intervention in disease states associated with altered nutrient microenvironments, including infection and cancer.

Together our four groups of authors presented here provide a fantastic discussion of the metabolic pressures and potential in the dynamic interaction between the mammalian host and diverse microbial pathogens. We hope you enjoy this collection of articles, and we also look forward to sharing the next instalment: the influence of immunometabolism during specific pathogenic infections.