Epigenetic and metabolic programming of innate immunity in sepsis

Abstract

Sepsis, the 10th leading cause of death, is the most expensive condition in the United States. The immune response in sepsis transitions from hyperinflammatory to a hypoinflammatory and immunosuppressive phase; individual variations regarding timing and overlap between hyper- and hypoinflammation exist in a number of patients. While one third of the sepsis-related deaths occur during hyperinflammation, majority of the sepsis-mortality occurs during the hypoinflammatory phase. Currently, no phase-specific molecular-based therapies exist to treat sepsis. Coordinated epigenetic and metabolic perturbations orchestrate this shift from hyper- to hypoinflammation in innate immune cells during sepsis. These epigenetic and metabolic changes during sepsis progression and therapeutic opportunities they pose are described in this review.

Keywords: Epigenetic programming; hyperinflammation; hypoinflammation; immunosuppression; metabolism; sepsis; septic shock.

Figure 1.

Immune response in sepsis: immune response in sepsis transitions from hyperinflammatory to a hypoinflammatory phase followed by resolution. Hyperinflammatory phase of immune cell activation is characterized by endotoxin responsive state with cytokine storm is cytotoxic to immune and other organ cells. Hypoinflammatory phase is characterized by endotoxin tolerance and immunosuppression. Hyper- and hypoinflammatory phases are associated with profound departure from homeostasis. Restoration of homeostasis is achieved during the resolution phase of sepsis.

Figure 2.

Epigenetic modifications: heterochromatin constitute of tightly packaged DNA around histone backbone, making DNA inaccessible to transcription factors. In response to cell signaling including stress, euchromatin formation (unwinding) occurs making DNA accessible for transcription factors. Several histone modifications on histone tails including acetylation, methylation, ubiquitination, and sumoylation modulate winding and unwinding of chromatin. Lysine (K) acetylation (AC) is mostly associated with euchromatin formation while methylation with silencing of DNA (not shown).

Figure 3.

Metabolic changes of during sepsis. (a) Aerobic glycolysis by immune cells during hyperinflammatory phase of sepsis. During this phase, there is inhibition of oxidative phosphorylation and selective increase in PPP. Aerobic glycolysis provides ATP generation fulfilling the “high energy” demand of cells. In addition, there is generation of NADPH and Rib-5-phosphate to fulfil the “activation of effector immunity” and “cell regeneration” to support pathogenic killing, as detailed in the text. (b) The fatty acid uptake during the hypoinflammatory and cytoprotective response of sepsis. This is associated with increased CD36 expression on immune cell surface. Hypoinflammatory phase is associated with increased β-oxidation and tricarboxylic acid (TCA) cycle to produce energy for cell survival.

Figure 4.

Summary of epigenetic and metabolic changes of sepsis: epigenetic and metabolic changes coordinate to change hyper- to hypoinflammatory phase in immune cells.