Foundations of Immunometabolism and Implications for Metabolic Health and Disease

Abstract

Highly ordered interactions between immune and metabolic responses are evolutionarily conserved and paramount for tissue and organismal health. Disruption of these interactions underlies the emergence of many pathologies, particularly chronic non-communicable diseases such as obesity and diabetes. Here, we examine decades of research identifying the complex immunometabolic signaling networks and the cellular and molecular events that occur in the setting of altered nutrient and energy exposures and offer a historical perspective. Furthermore, we describe recent advances such as the discovery that a broad complement of immune cells play a role in immunometabolism and the emerging evidence that nutrients and metabolites modulate inflammatory pathways. Lastly, we discuss how this work may eventually lead to tangible therapeutic advancements to promote health.

NK cell metabolism

“…Immunometabolism is one of the hottest topics in Immunology today. Although only 10 years old, the field of immunometabolism has already generated findings that have potential to impact on human health . This review is not designed to cover all aspects of immunometabolism as there are many excellent reviews in the literature that cover the topic in great depth .…”

Cancer metabolism gets physical

“…Although the metabolic phenotype of the tumor cells themselves may be responsible for these observations, it is likely that the interactions with other cell types present in the tumor microenvironment, but lacking in vitro, play a critical role (8). For example, stromal cell metabolism is key to generating a favorable nutrient and energy landscape for tumors, and, more recently, similar observations have also been made for immune cells (9). Our understanding of the role of molecular and cellular changes in the microenvironment is advancing at a rapid pace.…”

“…In addition, a variety of other conditions further augment complexity. In particular, metabolic rewiring can directly affect immunity and vice versa (9). This interplay has potentially far-reaching implications not only for the growing field of immunooncology but also for obesity-associated cancers, which tend to be more aggressive and occur in microenvironments that exhibit intrinsically impaired immunity and metabolism (17).…”

“…These challenges might be overcome by complementing PDX models with physiologically relevant in vitro assays that can be used to quickly and accurately perform high-throughput screening with potential therapeutic agents and provide mechanistic information to guide treatment. As researchers develop new methods for maintaining the full complement of immune cells in cultured systems, advanced in vitro models can be used to examine the impact of immune cells and immune targeted therapies on tumor metabolism and the microenvironment as well as their role in tumor clearance, questions that cannot be readily addressed in immunodeficient murine systems (9, 51, 52). …”

Mitochondrial dysfunction and damage associated molecular patterns (DAMPs) in chronic inflammatory diseases

“…Mitochondrial dysfunction perturbs alteration of adenosine triphosphate (ATP)/adenosine diphosphate (ADP) ration, which, in turn, activates adenosine monophosphate-activated protein kinase (AMPK), a master regulator of cellular energy homeostasis. Indeed, a highly ordered interactions between immune and metabolic responses have been demonstrated in multiple studies, identifying the complex immunometabolic signaling networks and the cellular and molecular events which underlie the development of chronic inflammatory diseases (Hotamisligil, 2017). …”