Immunometabolism of pro-repair cells

Abstract

Immune cell populations determine the balance between ongoing damage and repair following tissue injury. Cells responding to a tissue-damaged environment have significant bioenergetic and biosynthetic needs. In addition to supporting these needs, metabolic pathways govern the function of pro-repair immune cells, including regulatory T cells and tissue macrophages. In this Review, we explore how specific features of the tissue-damaged environment such as hypoxia, oxidative stress, and nutrient depletion serve as metabolic cues to promote or impair the reparative functions of immune cell populations. Hypoxia, mitochondrial DNA stress, and altered redox balance each contribute to mechanisms regulating the response to tissue damage. For example, hypoxia induces changes in regulatory T cell and macrophage metabolic profiles, including generation of 2-hydroxyglutarate, which inhibits demethylase reactions to modulate cell fate and function. Reactive oxygen species abundant in oxidative environments cause damage to mitochondrial DNA, initiating signaling pathways that likewise control pro-repair cell function. Nutrient depletion following tissue damage also affects pro-repair cell function through metabolic signaling pathways, specifically those sensitive to the redox state of the cell. The study of immunometabolism as an immediate sensor and regulator of the tissue-damaged environment provides opportunities to consider mechanisms that facilitate healthy repair of tissue injury.

Figure 1. Overview of pathways involved with immunometabolism and their links to protein and cell function.

Both cytosolic and mitochondrial reactions generate important molecules that can modulate protein structure and function, regulate enzymatic reactions, and control cell fate and function. ACLY, ATP-citrate lyase; ETC, electron transport chain; GLS, glutaminase; α-KG, α-ketoglutarate; LDH, lactate dehydrogenase; l-(S)-2-HG, l-(S)-2-hydroxyglutarate; MDH, malate dehydrogenase; mtDNA, mitochondrial DNA; OAA, oxaloacetate; PDH, pyruvate dehydrogenase.

Figure 2. Immunometabolic mechanisms at play in the tissue-damaged environment.

Hypoxia, oxidative stress, and nutrient depletion combine to cause significant changes in metabolism. Metabolic programming (blue text), mtDNA stress (red text), and redox state (orange text) are highlighted in their effects on pro-repair cells.

Figure 3. Metabolic features of the tissue-damaged environment.

Acute lung injury and its clinical correlate the acute respiratory distress syndrome (ARDS) represent a prototypical tissue-damaged environment. Inflammatory signals, including TLR activation, lead to neutrophil recruitment. Neutrophils and other cells consume oxygen and nutrients and cause tissue damage by release of various substances, importantly ROS. Combined with the physiologic effects of tissue injury, the result is an environment characterized by hypoxia, oxidative stress, and nutrient depletion. AEC, alveolar epithelial cell; NET, neutrophil extracellular trap.