Metabolic regulation of the immune system in health and diseases: mechanisms and interventions

Abstract

Metabolism, including glycolysis, oxidative phosphorylation, fatty acid oxidation, and other metabolic pathways, impacts the phenotypes and functions of immune cells. The metabolic regulation of the immune system is important in the pathogenesis and progression of numerous diseases, such as cancers, autoimmune diseases and metabolic diseases. The concept of immunometabolism was introduced over a decade ago to elucidate the intricate interplay between metabolism and immunity. The definition of immunometabolism has expanded from chronic low-grade inflammation in metabolic diseases to metabolic reprogramming of immune cells in various diseases. With immunometabolism being proposed and developed, the metabolic regulation of the immune system can be gradually summarized and becomes more and more clearer. In the context of many diseases including cancer, autoimmune diseases, metabolic diseases, and many other disease, metabolic reprogramming occurs in immune cells inducing proinflammatory or anti-inflammatory effects. The phenotypic and functional changes of immune cells caused by metabolic regulation further affect and development of diseases. Based on experimental results, targeting cellular metabolism of immune cells becomes a promising therapy. In this review, we focus on immune cells to introduce their metabolic pathways and metabolic reprogramming, and summarize how these metabolic pathways affect immune effects in the context of diseases. We thoroughly explore targets and treatments based on immunometabolism in existing studies. The challenges of translating experimental results into clinical applications in the field of immunometabolism are also summarized. We believe that a better understanding of immune regulation in health and diseases will improve the management of most diseases.

Fig. 1

Timeline for metabolic regulation of the immune system. Events mainly involving new findings or important reviews on metabolic pathways are in green boxes. Events mainly focusing on macrophages and T cells are are in bule and purple boxes. Light green boxes show events involving important molecules in immunometabolism. A light red box shows a special event that the concept of immunometabolism has been introduced and discussed in metabolic diseases in 2011. Before 2011, the studies on Warburg effect in cancer and metabolic characteristics of macrophages both contributes to the development of the immunometabolism field. In the last more than twenty years, the concept immunometabolism has been generally accepted and studied. Abbreviation: OXPHOS oxidative phosphorylation, mTOR mechanistic target of rapamycin, HIF-1α hypoxia-inducible factor 1α, PI3K phosphatidyl-inositol 3 kinase

Fig. 2

Metabolic pathways in immune cells. The most reported metabolic pathways in immune cells are glycolysis, especially aerobic glycolysis, fatty acid oxidation (FAO), fatty acid synthesis (FAS), and oxidative phosphorylation (OXPHOS). Aerobic glycolysis and FAS are always active in immune cells with proinflammatory phenotypes including M1 macrophages and effector T cells, while FAO and OXPHOS are always active in immune cells with anti-inflammatory phenotypes including M2 macrophages and regulatory T (Treg) cells. Pentose phosphate pathway (PPP) is a branch of glycometabolism but studies on immune cells are not enough. Glutamine is the most important amino acid in immunometabolism, of which the metabolism is associated with other pathways by α-ketoglutarate

Fig. 3

Metabolic regulation of immune cells in cancer. During the development and progression of cancer, dramatic metabolic reprogramming happens in tumor cells and immune cells. Tumor cells have high metabolic demand and metabolic competition with immune cells. The tumor microenvironment is an immunosuppressive environment with the proportion of proinflammatory immune cells decreasing and anti-inflammatory cells increasing. Tumor derived-lactate is an important metabolite to regulate the phenotypes of immune cells. M2 macrophages have an abnormally high capacity to take up glucose, while glucose metabolism is reduced in effector T cells and glycolysis. Nuclear factor-kappaB (NF-κB), Toll-like receptor-2 (TLR2) and forkhead/winged helix transcriptional factor P3 (FoxP3) can regulate glucose metabolism. Lipid accumulation is upregulated in M2 macrophages and effector T cells, and lipid synthesis is upregulated in regulatory T (Treg) cells mediated by sterol regulatory-element binding proteins (SREBPs). Fatty acid oxidation (FAO) is active in M2 macrophages, with peroxisome proliferator-activated receptor γ (PPARγ) and CD36 involved in the regulation. Glutamine metabolism and serine synthesis is increased in M2 macrophages, and protein kinase RNA-like ER kinase can upregulate the serine synthesis. In effector T cells, glutamine uptake is reduced

Fig. 4

Metabolic regulation of immune cells in autoimmune diseases. Systemic lupus erythematosus (SLE), inflammatory bowel diseases (IBDs) and rheumatoid arthritis (RA) are typical representatives of autoimmune diseases. Generally, affected sites of autoimmune diseases are dominated by immune cells with proinflammatory phenotypes. The metabolism of immune cells with proinflammatory phenotypes are active in the context of autoimmune diseases. Mechanistic target of rapamycin complex 1 (mTORC1)/hypoxia-inducible factor 1α (HIF-1α) signaling, mechanistic target of rapamycin complex 2 (mTORC2)/peroxisome proliferator-activated receptor γ (PPARγ) signaling, Zip8, glucose transporter type 1 (GLUT1), cellular myelocytomatosis oncogene (c-Myc), lactate dehydrogenase A (LDHA), and interleukin-27 (IL-27) have been proved to participate in the regulation of glycometabolism. Nuclear factor-kappaB (NF-κB) and CD36 can regulate fatty acid oxidation (FAO). In RA, lactate from synovial tissues is involved in regulating the metabolism of immune cells

Fig. 5

Metabolic regulation of immune cells in metabolic diseases. Chronic low-grade inflammation has been considered as an important trait of metabolic diseases. Obesity, type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD) are typical representatives of metabolic diseases. Tumor necrosis factor (TNF)-α from adipocytes can induce M1 macrophage polarization, and insulin supports interleukin (IL)-1-producing T helper (Th1) cells cell differentiation. Generally, in immune cells with proinflammatory phenotype, the metabolic pathways are upregulated. Glucose transporter type 1 (GLUT1), Hypoxia-inducible factor-1α (HIF-1α) and pyruvate kinase muscle isozyme M2 (PKM2) are involved in regulating the metabolism of immune cells. After being activated, M1 macrophages can infiltrate adipose tissue, cause inflammation in islets and induce inflammation in the liver. Pro-inflammatory cytokines and chemokines produced by immune cells participate in disease progression