Lifestyle-associated pathologies have reached epidemic proportions and urgent action is needed to protect the public from unhealthy diets. Here, the authors describe how the Western diet has long-lasting effects on the immune system that promote chronic metabolic inflammatory diseases.
Focus on immunometabolism
Over the past decade, “immunometabolism” has become one of the most exciting areas of translational research. Metabolic processes regulate immune cell responses in healthy individuals as well as during infection, cancer, autoimmunity and obesity. Moreover, immune responses are shaped not only by host metabolites, but also by metabolites derived from the microbiota and infectious agents. These discoveries are paving the way for novel therapies for chronic inflammatory and autoimmune diseases, as well representing a new class of cancer immunotherapies.
In this Focus in Nature Reviews Immunology, leading experts discuss the latest developments in the field.
Comments & Research Highlights
A new study shows that immune activation after infection involves competition for energy with physiological programmes such as maintaining a normal body temperature. This trade-off favours immune tolerance as a strategy for host defence.
Tumour cells induce membrane cholesterol efflux from macrophages, leading to macrophage acquisition of a pro-tumour phenotype.
During inflammation, IL-17 rewires metabolic processes in lymph node fibroblastic reticular cells, thereby supporting their survival and population expansion.
Liver macrophages produce the non-inflammatory factor IGFBP7, which has direct effects on liver metabolism in metabolic disease without requiring a switch to a pro-inflammatory phenotype.
Doreen Cantrell describes a 2005 paper by Graham Hardie and colleagues showing that Ca2+–calmodulin-dependent protein kinase kinases could phosphorylate and activate AMPK, which suggested a biochemical link between T cell receptor signalling and ATP production.
Reviews & Perspectives
During an immune response, macrophage metabolism is diverted to produce the metabolite itaconate, which has anti-inflammatory effects. This Review recounts the story of itaconate, from its discovery to its potentially far-reaching consequences for immunity, host defence and tumorigenesis.
As in other immune cells, the metabolic pathways in natural killer (NK) cells must be configured to meet the demands of their effector functions. This Review describes the specific metabolic requirements for NK cell responses and how defects in NK cell metabolism may contribute to NK cell dysfunction in chronic disease.
Different lineages of macrophages respond divergently to immune stimuli and microbial infection. This Review explores our current knowledge of how the different metabolic states of macrophage lineages impact the control or progression of intracellular bacterial infections.
The intestinal microbiota profoundly shapes host physiology through its production of small molecules and metabolites. Here, Honda and colleagues discuss how these microbial products shape immune function. They further consider the potential of ‘mining’ the microbiota for new microbial and metabolite-based immunotherapies.
In this Review, Erika Pearce and colleagues detail the metabolic changes that occur in the tumour microenvironment, explaining how these shape immune cell function at these sites. They highlight the potential of targeting these metabolic pathways to treat patients with cancer
B cells have many unique metabolic features. Markus Müschen highlights these in this Opinion article and proposes the concept of three key metabolic gatekeepers that protect against B cell-associated autoimmunity and lymphomas.
This Review discusses the importance of autophagy in controlling immune cell differentiation and homeostasis. The authors consider the diverse mechanisms through which autophagy functions to shape the immune system, highlighting its role in the dynamic regulation of metabolism.
Lionel Ivashkiv discusses new insight into the functions of IFNγ and summarizes our current understanding of IFNγ receptor signalling. In particular, the author focuses on recent studies on how IFNγ influences autoimmunity, immunometabolism, neurological diseases and cancer immunotherapy.
Here, the authors introduce the idea that a spectrum of metabolic states of immune cells can provide a basis for categorizing human diseases. They explore the metabolic and interlinked signalling requirements of T cells responding to acute infection and how metabolic reprogramming of T cells is linked to disease.
Does mitochondrial metabolism simply support the bioenergetic and biosynthetic needs of committed immune cells, or does it also control their fate? In this Review, Chandel and colleagues explore variations in mitochondrial metabolism across different immune cells and discuss how mitochondria can act as important signalling organelles to dictate immune cell function.
Immunometabolism is emerging an important area of immunological research, but for many immunologists the complexity of the field can be daunting. Here, the authors provide an overview of six key metabolic pathways that occur in immune cells and explain what is known (and what is still to be uncovered) concerning their effects on immune cell function.
T cell differentiation and metabolism are intimately linked. This article describes how T cell receptor-induced transcription factors cooperate with canonical nutrient-sensing pathways to integrate antigen-specific and metabolic signals and appropriately modulate adaptive immune responses.
This Review describes how key metabolic processes are differentially regulated in dendritic cells (DCs), both during their development and during their participation in active immune responses. The authors discuss the importance of these changes in cellular metabolism for DC function and also explain how both intracellular and extracellular metabolites shape DC biology.
In 2017, studies of cellular metabolism broadly permeated immunological research. Accumulating data support the view that understanding how metabolism regulates immune cell function could provide new therapeutic opportunities for the many diseases associated with immune system dysregulation.
The field of immunometabolism (both on the cellular as well as on the organismal level) is advancing rapidly. This article highlights several studies from 2018 that examine how immune cells can regulate systemic metabolism, as well as studies of the impact of organismal metabolism on the immune system in conditions such as obesity and cancer.