Energy metabolism and rheumatic diseases: from cell to organism

Abstract

In rheumatic and other chronic inflammatory diseases, high amounts of energy for the activated immune system have to be provided and allocated by energy metabolism. In recent time many new insights have been gained into the control of the immune response through metabolic signals. Activation of immune cells as well as reduced nutrient supply and hypoxia in inflamed tissues cause stimulation of glycolysis and other cellular metabolic pathways. However, persistent cellular metabolic signals can promote ongoing chronic inflammation and loss of immune tolerance. On the organism level, the neuroendocrine immune response of the hypothalamic-pituitary adrenal axis and sympathetic nervous system, which is meant to overcome a transient inflammatory episode, can lead to metabolic disease sequelae if chronically activated. We conclude that, on cellular and organism levels, a prolonged energy appeal reaction is an important factor of chronic inflammatory disease etiology.

Figure 1

Metabolic pathways in T cells. T-cell activation by T-cell receptor (TCR)/CD28 co-stimulation and growth factors/cytokines such as IL-2 or IL-7 activate AKT through phosphoinositide 3-kinase (PI3K) induction in a similar manner to insulin, inducing increase of glucose uptake and glycolysis. The switch to glycolysis allows production of the requisite ATP and biosynthetic substrates that are required for proliferation, cytokine synthesis and other T-cell functions. AKT activates mammalian target of rapamycin (mTOR), which increases the expression of amino acid transporters and glycolysis. Inflammation can also lead to hypoxia and reduced nutrient supply. Low ATP levels activate AMP activated protein kinase (AMPK), which upregulates catabolic processes, such as fatty acid oxidation, and downregulates anabolic metabolism. AMPK can inhibit mTOR via raptor and lead to cell-cycle arrest. Hypoxia induces hypoxia inducible factor (HIF) expression via mTOR activity. HIF-1 forms tertiary complexes with RORγt and p300, and enhances inflammation-promoting Th17 cell development through recruitment to the IL-17 promoter or upregulation of glycolysis. Concurrently, HIF-1 attenuates inflammation-restricting regulatory T cell (Treg) development by binding Foxp3. HIF-1 induces migration inhibitory factor (MIF), which in turn causes HIF-1 expression via the MIF receptor (MIF-R) in a positive feedback loop. The AMPK stimulator metformin and the mTOR inhibitor rapaymcin are able to augment fatty acid oxidation and can increase Treg generation.