The Metabolic Basis of Immune Dysfunction Following Sepsis and Trauma

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.

Keywords: infection; metabolic reprogramming; mitochondria; sepsis; trained immunity; trauma.

Figure 1

Metabolic reprogramming of leukocytes. Inflammatory stimulation of leukocytes, specifically monocytes and macrophages, with Toll-like receptor 4 (TLR4) ligands like lipopolysaccharide, has been shown to rewire mitochondrial metabolic pathways including upregulation of immunoresponsive gene 1 (Irg1) leading to increased itaconate generation, and increased accumulation of other TCA cycle metabolites including succinate, fumarate, malate, and citrate which continue to be replenished via additional pathways including glutamine anapleurosis and aspartate-arginosuccinate shunt. Itaconate produced by Irg1 inhibits succinate dehydrogenase, which causes an increase in mitochondrial reactive oxygen species (mROS). Itaconate and mROS augment antimicrobial capacity of leukocytes.

Figure 2

Generation of innate immune memory using microbial ligands. Initial challenge with microbial ligands such as lipopolysaccharide, monophosphoryl lipid A, CpG, β-glucan potently stimulates host innate effector immune responses in cells such as neutrophils, monocytes, and macrophages, leading to the reprogramming of their metabolic and epigenetic status. Upon re-exposure of the initially primed host with a secondary inflammatory stimulus or infectious challenge, there occurs a heightened innate immune response against invading microbes via increased immune cell recruitment leading to improved microbial clearance and survival. This phenomenon is termed as innate immune memory.