[Immunometabolism in Sepsis]

Abstract

Immunometabolism is a fascinating field of research that investigates the interactions between metabolic processes and the immune response. This intricate connection plays a pivotal role in regulating inflammatory reactions and consequently exerts a significant impact on the course of sepsis. The proinflammatory response during an immune reaction is closely tied to a high energy demand in immune cells. As a result, proinflammatory immune cells rapidly require substantial amounts of energy in the form of ATP, necessitating a fundamental and swift shift in their metabolism, i.e., their means of generating energy. This entails a marked increase in glycolysis within the proinflammatory response, thereby promptly meeting the energy requirements and providing essential metabolic building blocks for the biosynthesis of macromolecules. Alongside glycolysis, there is heightened activity in the pentose phosphate pathway (PPP). The PPP significantly contributes to NADPH production within the cell, thus maintaining redox equilibrium. Elevated PPP activity consequently leads to an increased NADPH level, resulting in enhanced production of reactive oxygen species (ROS) and nitric oxide (NO). While these molecules are crucial for pathogen elimination, an excess can also induce tissue damage. Simultaneously, there are dual interruptions in the citric acid cycle. In the cellular resting state, the citric acid cycle acts as a sort of "universal processor", where metabolic byproducts of glycolysis, fatty acid breakdown, and amino acid degradation are initially transformed into NADH and FADH2, subsequently yielding ATP. While the citric acid cycle and its connected oxidative phosphorylation predominantly generate energy at rest, it becomes downregulated in the proinflammatory phase of sepsis. The two interruptions lead to an accumulation of citrate and succinate within cells, reflecting mitochondrial dysfunction. Additionally, the significantly heightened glycolysis through fermentation yields lactate, a pivotal metabolite for sepsis diagnosis and prognosis. Conversely, cells in an anti-inflammatory state revert to a metabolic profile akin to the resting state: Glycolysis is attenuated, PPP is suppressed, and the citric acid cycle is reactivated. Of particular interest is that not only does the immune reaction influence metabolic pathways, but this connection also operates in reverse. Thus, modulation of metabolic pathways also modulates the immunity of the corresponding cell and thereby the state of the immune system itself. This could potentially serve as an intriguing avenue in sepsis therapy.