Immunometabolism first appears in academic literature in 2011, where it is defined as "an emerging field of investigation at the interface between the historically distinct disciplines of immunology and metabolism.
"[3] A later article defines immunometabolism as describing "the changes that occur in intracellular metabolic pathways in immune cells during activation".
[4] Broadly, immunometabolic research records the physiological functioning of the immune system in the context of different metabolic conditions in health and disease.
These studies can cover molecular and cellular aspects of immune system function in vitro, in situ, and in vivo, under different metabolic conditions.
All of the aforementioned molecules together control the most important metabolic pathways in cells like glycolysis, krebs cycle or oxidative phosphorylation.
[7][6] mTORC2 enhances glycolysis as well, but in contrast to mTORC1, it activates akt, which in turn promotes glucose transporter 1 (GLUT1) membrane deposition.
[6] Furthermore, it activates ULK complex, phosphorylates p53 and acetyl-CoA carboxylase (ACC), which promotes autophagy, cell cycle arrest and fatty acids oxidation respectively.
On the contrary, cells whose main function is proliferation, synthesis of different molecules or propagation of inflammation often prefer glycolysis as a source of energy and metabolites.
[11][4] Although, it is important to note that complete suppression of glycolysis leads to enolase (a glycolytic enzyme) binding to a splice variant of Foxp3, which effectively compromises peripheral Tregs abilities to act as immunosuppressive cells.
For this development the engagement of costimulatory molecules, like CD28, appears to be crucial, as the co-stimulation manifests in mitochondrial morphology, thus allowing for higher oxidative phosphorylation but also retaining the potential to quickly revert to glycolysis.
[10][4] How the fully operational Krebs cycle exactly translates to M2 macrophages functions is still poorly understood, but the upregulated pathways allow for production of intermediates (mainly acetyl-CoA and S-adenosyl methionine), which are needed for histone modifications of genes targeted by IL-4 signalling.
[20][21] The metabolic alterations on immune system regulation have provided unique insights into disease pathogenesis and development, as well as potential therapeutic targets.
This phenomenon affects both the acute and late stages of the disease, playing a critical role in the immune response during sepsis.
Although there is a strong inflammatory response during the early phase of sepsis,[25][26] immunometabolic paralysis may appear later on and is linked to a bad prognosis for the patient.
Shih Chin Cheng and colleagues have conducted recent research that explores the complex interplay between cellular metabolism and the immune response in sepsis.
Although few medicines possessing metabolic-regulatory properties have been investigated, the study emphasizes how important it is to comprehend and treat immunometabolic paralysis in order to improve outcomes for individuals suffering from sepsis.
[25] Conclusion To sum up, the research conducted by Cheng and colleagues provides significant understanding of the intricate relationship between immune response and cellular metabolism in sepsis.
A crucial role for immunometabolic paralysis—a condition marked by impaired energy metabolism—in the development and cure of sepsis is revealed.
It appears that more investigation and testing of therapeutic approaches aimed at cellular metabolism will help to improve the management of sepsis.