Fine tuning of immunometabolism for the treatment of rheumatic diseases

Abstract

All immune cells depend on specific and efficient metabolic pathways to mount an appropriate response. Over the past decade, the field of immunometabolism has expanded our understanding of the various means by which cells modulate metabolism to achieve the effector functions necessary to fight infection or maintain homeostasis. Harnessing these metabolic pathways to manipulate inappropriate immune responses as a therapeutic strategy in cancer and autoimmunity has received increasing scrutiny by the scientific community. Fine tuning immunometabolism to provide the desired response, or prevent a deleterious response, is an attractive alternative to chemotherapy or overt immunosuppression. The various metabolic pathways used by immune cells in rheumatoid arthritis, systemic lupus erythematosus and osteoarthritis offer numerous opportunities for selective targeting of specific immune cell subsets to manipulate cellular metabolism for therapeutic benefit in these rheumatologic diseases.

Figure 1. Metabolic reprogramming of immune cell populations matches immunological function

Naive T cells, resting B cells and macrophages utilize a catabolic and oxidative metabolic programme. After stimulation via antigen receptor with co-stimulation or through pattern-recognition receptors such as Toll-like receptors (TLRs), these immune cells undergo metabolic reprogramming. Effector lymphocytes or inflammatory macrophages induce an anabolic meta bolic programme with highly increased nutrient uptake for glycolysis and glutamine metabolism. Regulatory cells or alternatively activated macrophages, by contrast, primarily utilize a programme of lipid and pyruvate oxidation. These programmes are important to the function of each subset; if the cellular metabolism does not match the cell fate, immune cells will fail to gain appropriate functional capacity. BCR, B cell receptor; CTLA-4, cytotoxic T lymphocyte protein 4; HIF, hypoxia-inducible factor; mTOR, mechanistic target of rapamycin; PD-1, programmed cell death protein 1; PGCla, peroxisome proliferator-activated receptor γ co-activator 1-α; TCR, T cell receptor; T_reg cell, regulatory T cell.

Figure 2. Metabolic processes to target in the treatment of rheumatologic diseases

Metabolic areas and key current or potential targets for drugs to modify immunometabolism and shift immune cell subsets and fate are indicated. 2-DG, 2-deoxy-d-glucose; ASCT2, solute carrier family 1 member 5; DCA, dichloroacetate; ETC, electron transport chain; GLUT1, glucose transporter 1; HIF-1α, hypoxia-inducible factor 1α; HK, hexokinase; LDHA, lactate dehydrogenase A; mTORC, mechanistic target of rapamycin complex; PDHK1, pyruvate dehydrogenase kinase 1; PFKFB3. 6-Phosphofructo 2-kinase/fructose-2,6-bisphosphatase 3.