Metabolic Reprogramming and Its Regulatory Mechanism in Sepsis-Mediated Inflammation

Abstract

Sepsis is a systemic inflammatory disease caused by an infection that can lead to multiple organ failure. Sepsis alters energy metabolism, leading to metabolic reprogramming of immune cells, which consequently disrupts innate and adaptive immune responses, triggering hyperinflammation and immunosuppression. This review summarizes metabolic reprogramming and its regulatory mechanism in sepsis-induced hyperinflammation and immunosuppression, highlights the significance and intricacies of immune cell metabolic reprogramming, and emphasizes the pivotal role of mitochondria in metabolic regulation and treatment of sepsis. This review provides an up-to-date overview of the relevant literature to inform future research directions in understanding the regulation of sepsis immunometabolism. Metabolic reprogramming has great promise as a new target for sepsis treatment in the future.

Keywords:

• immune cell
• hyperinflammation
• immunosuppression
• immunometabolism
• mitochondria

Abbreviations

PRR, pathogen recognition receptor; PAMP, pathogen-associated molecular pattern; DAMP, damage-associated molecular pattern; TLR, Toll-like receptor; NLR, NOD-like receptor; RLR, RIG-I-like receptor; PPP, pentose phosphate pathway; NADPH, reduced nicotinamide adenine dinucleotide phosphate; NET, neutrophil extracellular traps; NOX, NADPH oxidase; ROS, reactive oxygen species; DC, dendritic cells; LPS, lipopolysaccharide; mTOR, mammalian target of rapamycin; HIF-1α, hypoxia-inducible factor-1α; GLUT1, glucose transporter 1; LDH, lactate dehydrogenase; PFKFB3, fructose-2,6-bisphosphatase 3; AMPK, adenosine 5’-monophosphate-activated protein kinase; FAO, fatty acid oxidation; OXPHOS, oxidative phosphorylation; IFN-γ, interferon-gamma; HK1, hexokinase 1; PKM2, pyruvate kinase M2; PPAR-γ, peroxisome proliferator-activated receptor γ; PDHC, pyruvate dehydrogenase complex; MDSCs, myeloid-derived suppressor cells; YAP, Yes-associated protein; PGC-1α, PPAR-γ coactivator 1 alpha; CaMK-IV, Ca/calmodulin-dependent protein kinase IV; UCP2, uncoupling protein 2; ITA, Itaconate.

Acknowledgments

This work was supported by the National Nature Science Foundation of China (81930057, 82072170, 82172201); Shanghai Rising Star Program (22QA1411700); Youth Medical Talents-Specialist Program; CAMS Innovation Fund for Medical Sciences (2019-I2M-5-076), Achievements Supportive Fund (2018-CGPZ-B03).

Disclosure

The authors report no conflicts of interest in this work.