Metabolic reprogramming consequences of sepsis: adaptations and contradictions

Abstract

During sepsis, the importance of alterations in cell metabolism is underappreciated. The cellular metabolism, which has a variable metabolic profile in different cells and disease stages, is largely responsible for the immune imbalance and organ failure associated with sepsis. Metabolic reprogramming, in which glycolysis replaces OXPHOS as the main energy-producing pathway, is both a requirement for immune cell activation and a cause of immunosuppression. Meanwhile, the metabolites produced by OXPHOS and glycolysis can act as signaling molecules to control the immune response during sepsis. Sepsis-induced "energy shortage" leads to stagnated cell function and even organ dysfunction. Metabolic reprogramming can alleviate the energy crisis to some extent, enhance host tolerance to maintain cell survival functions, and ultimately increase the adaptation of cells during sepsis. However, a switch from glycolysis to OXPHOS is essential for restoring cell function. This review summarized the crosstalk between metabolic reprogramming and immune cell activity as well as organ function during sepsis, discussed the benefits and drawbacks of metabolic reprogramming to show the contradictions of metabolic reprogramming during sepsis, and assessed the feasibility of treating sepsis through targeted metabolism. Using metabolic reprogramming to achieve metabolic homeostasis could be a viable therapy option for sepsis.

Keywords: Glycolysis; Immunosuppression; MODS; Metabolic reprogramming; OXPHOS; Sepsis; Tolerance.

Fig. 1

The crosstalk between metabolic reprogramming and immune cells activities. Immune cells rely mainly on OXPHOS for ATP production in the resting state. During sepsis, activated immune cells rely on increased glycolysis for ATP and various biosynthetic materials, such as Ru-5-P, DHAP, and G-3-P, to promote immune cell differentiation and proliferation. Macrophages differentiate into M1-type macrophages that promote inflammation and anti-inflammatory macrophages are differentiated into M2. T cells differentiate into pro-inflammatory effector T cells and anti-inflammatory regulatory T cells. Pro-inflammatory cells secrete large amounts of inflammatory factors (IL-6, IL-1β, and TNF-α) causing a host inflammatory response, at which time the balance between OXPHOS and glycolysis can still be maintained. However, when glycolysis is further enhanced, the balance is upset and lactate suppresses pro-inflammatory response and promotes anti-inflammatory response through various mechanisms, ultimately resulting in immunosuppression. GLUT1 glucose transporter protein 1, PFKFB3 fructose-2,6-bisphosphatase 3, HK2 hexokinase 2, PKM2 pyruvate kinase M2, LDH lactate dehydrogenase, DHAP dihydroxyacetone phosphate, G-3-P glyceraldehyde 3-phosphate, 3-P-G 3-phosphoglycerate, Glu-6-P glucose 6-phosphate, Fru-1,6-P 1,6-Fructose diphosphate, PPP pentose phosphate pathway, MCT4 monocarboxylate transporter 4, M0 Macrophage, Th1,Th2 effector T cells, Tregs regulatory T cells, ARG1 arginase 1, MGL1 Macrophage galactose-type lectin 1

Fig. 2

Metabolic reprogramming promotes tissue tolerance to increase organ cell adaptation during sepsis. Under normal conditions, cells obtain ATP from OXPHOS and glycolysis. Resting Immune cells have fewer energy requirements and therefore most of the energy is allocated to organ cells to support functional activities. In sepsis, ATP is preferentially allocated to immune cells to support immune activation for clearing the pathogens, which results in less ATP for organ cells. To reduce energy consumption, organ cells shut down functional activities and use ATP as much as possible to maintain cell life activities, which leads to stagnation in organ cell function even MODS. This is an adaptation mechanism of the host during sepsis. When OXPHOS is suppressed, enhanced glycolysis rapidly supplies ATP to maintain cellular survival and encourages stronger tissue tolerance to adapt to sepsis more easily. It also provides an opportunity for cells to restore OXPHOS to promote recovery of cellular function. GLUT1 glucose transporter protein 1, PFKFB3 fructose-2,6-bisphosphatase 3, HK2 hexokinase 2, PKM2 pyruvate kinase M2, LDH lactate dehydrogenase, Glu-6-P glucose 6-phosphate, Fru-6-P Fructose 6-phosphate, MODS multi-organ dysfunction syndrome