The Metabolic Basis of Immune Dysfunction Following Sepsis and Trauma.

Margaret A Mcbride,Julia K Bohannon,Allison M Owen,Antonio Hernandez,Liming Luan,Edward R Sherwood,Tazeen K Patil,Naeem K Patil,Katherine R Burelbach,Cody L Stothers

doi:10.3389/fimmu.2020.01043

Abstract

Critically ill, severely injured and high-risk surgical patients are vulnerable to secondary infections during hospitalization and after hospital discharge. Studies show that the mitochondrial function and oxidative metabolism of monocytes and macrophages are impaired during sepsis. Alternatively, treatment with microbe-derived ligands, such as monophosphoryl lipid A (MPLA), peptidoglycan, or β-glucan, that interact with toll-like receptors and other pattern recognition receptors on leukocytes induces a state of innate immune memory that confers broad-spectrum resistance to infection with common hospital-acquired pathogens. Priming of macrophages with MPLA, CPG oligodeoxynucleotides (CpG ODN), or β-glucan induces a macrophage metabolic phenotype characterized by mitochondrial biogenesis and increased oxidative metabolism in parallel with increased glycolysis, cell size and granularity, augmented phagocytosis, heightened respiratory burst functions, and more effective killing of microbes. The mitochondrion is a bioenergetic organelle that not only contributes to energy supply, biosynthesis, and cellular redox functions but serves as a platform for regulating innate immunological functions such as production of reactive oxygen species (ROS) and regulatory intermediates. This review will define current knowledge of leukocyte metabolic dysfunction during and after sepsis and trauma. We will further discuss therapeutic strategies that target leukocyte mitochondrial function and might have value in preventing or reversing sepsis- and trauma-induced immune dysfunction.

Highlights

Serious infection is a major threat to critically ill patients and frequently precipitates sepsis, a complex disease spectrum that includes systemic inflammation and organ dysfunction
Cheng et al, showed that both bacterial and fungal sepsis leads to a shift in cellular metabolism toward glycolysis (Warburg effect), and leukocytes isolated from septic patients, as well as those treated with lipopolysaccharide (LPS), demonstrated a reduced oxygen consumption capacity signifying mitochondrial defects [31, 44]
We have reviewed the impact of sepsis on the mitochondrial function of innate leukocytes, and potential therapeutic strategies for reprogramming leukocyte metabolism to induce innate immune memory and restore host immune competency

Summary

Introduction

Serious infection is a major threat to critically ill patients and frequently precipitates sepsis, a complex disease spectrum that includes systemic inflammation and organ dysfunction. Recent studies demonstrate that sepsis-induced impairment of leukocyte mitochondrial function contributes to impaired antimicrobial immune responses and increased susceptibility to secondary infections [30, 31].

Results

Conclusion