The underlying molecular mechanisms that promote autoimmune diseases are multilayered and complex. Genetic background, single nucleotide polymorfisms, silent mutations and the surrounding enviroment tangle together and sort out as autoimmunities once the “cauldron is ignited” by specific triggers. In affected patients, the immune system attacks the body’s own tissue and the consequences are, for example, chronic inflammatory bowel diseases such as Crohn’s disease, type 1 diabetes, lupus, rheumatoid arthritis and chronic thyroiditis like the Hashimoto disease. Neurons are for sure at the top-list for glucose requirements among the other bodily cell types. Not everyone knows, however, that immune cells need large amounts of sugar in the form of glucose to perform their tasks. Like to other cells, they can take up glucose from the environment with the help of specialized transporters at their cell membrane.
Now, scientists at the Julius Maximilians University of Würzburg have succeeded in deciphering new details of these processes. Their work support the notion that excessive consumption of glucose directly promotes the pathogenic functions of certain cells of the immune system and that, conversely, that a calorie-reduced diet can have a beneficial effect on immune diseases. Based on these findings, they also identified new targets for therapeutic interventions: a specific blockade of glucose-depended metabolic processes in these immune cells can suppress excessive immune reactions. According to their data, people who consume sugar and other carbohydrates in excess over a long period of time have an increased risk of developing an autoimmune disease. Glucose uptake usaually happens by mean of specifica transportes called GLUTs.
Generally, most cells utilize GLUT1 primarily; the isoform GLUT4 is activated upn cellular stimulation with insulin. Scientists here found that the GLUT3, instead, fulfills additional metabolic functions in T cells besides the generating energy from sugar. In their study, the scientists focused on a group of cells of the immune system that have not been known for very long: T helper cells of type 17, also called Th17 lymphocytes, which play a central role in regulating (auto-) inflammatory processes. This lymphocyte subpopulation express lots of GLUT3 protein on their cell surface. Once taken up, glucose readily undergoes glycolysis, being metabolized into acetyl-coenzyme A (acetyl-CoA) in the cytoplasm. This metabolite translocated inside mitochondria, where enter the Krebs cycle and is converted to citric acid. Acetyl-CoA is also involved in the biosynthesis of lipids.
However, acetyl-CoA fulfills additional functions in inflammatory Th17 cells. The research team showed that this metabolic intermediate can also regulate the activity of various gene segments. It is indeed a cofactor for enzymes executing the process of protein acetylation. At least the 50% of protein acetylation happens inside the nucleus, being mediated by histone acetyltransferases (HATs). These enzymes are activated upon cellular stimulations e.g. with hormones, cytokines and growth factors. They modify histone proteins associated with DNA (nucleosomes), allowing their removal to start gene transcription. The opposite task is performed by the histeon deacetylases, that turn off gene expression (silincing). This way, one may understand that glucose consumption is directly linked to the activity of proinflammatory genes. The higher the glucose availability, the higher the chance to enhance gene expression over gene repression.
According to the researchers, theses new findings pave the way for the development of targeted therapy of autoimmune diseases. The so-called “metabolic reprogramming” of T cells opens new possibilities to treat autoimmune diseases without curtailing protective immune cell functions. For example, blocking GLUT3-dependent synthesis of acetyl-CoA by the dietary supplement hydroxy-citrate, which is used to treat obesity, can mitigate the pathogenic functions of Th17 cells and reduce inflammatory-pathological processes. This would be completely innovative, given that immunosuppressants such as methotrexate, mycophenolate mofetil and corticosteroids are generally used to treat autoimmune disorders. A bioenergetic approach, therefore, could prevent patients with autoimmune syndromes from encountering the numerous adverse effects caused by regular drugs.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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Scientific references
Cell Metab. 2022 Mar 15.
J Neuroimmunol. 2022 Jan; 362:577778.
Wu H et al. Front Pharmacol 2021 Dec; 12:734078.
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