Living with Yourself: Innate Lymphoid Cell Immunometabolism

Abstract

Innate lymphoid cells (ILCs) are tissue-resident sentinels of the immune system that function to protect local tissue microenvironments against pathogens and maintain homeostasis. However, because ILCs are sensitively tuned to perturbations within tissues, they can also contribute to host pathology when critical activating signals become dysregulated. Recent work has demonstrated that the crosstalk between ILCs and their environment has a significant impact on host metabolism in health and disease. In this review, we summarize studies that support evidence for the ability of ILCs to influence tissue and systemic metabolism, as well as how ILCs can be regulated by environmental changes in systemic host metabolism. We also highlight studies demonstrating how ILC- intrinsic metabolism influences their activation, proliferation, and homeostasis. Finally, this review discusses the challenges and open questions in the rapidly expanding field of ILCs and immunometabolism.

Keywords: diet; immunometabolism; innate lymphoid cells; microbiota; obesity.

Figure 1

Metabolic pathways utilized by innate lymphoid cells (ILCs) during homeostasis and activation. (A) Naive ILCs are generally thought to be quiescent and largely use metabolic pathways that efficiently metabolize glucose through glycolysis-linked mitochondrial oxidative phosphorylation (OxPhos) to generate energy in the form of adenosine triphosphate (ATP). However, during inflammation, ILCs respond to increased levels of proinflammatory cytokines that cause their activation and concomitant changes in cellular metabolism. (B) Activated natural killer (NK) cells respond to heighten levels of the cytokines IL-12, IL-18, and IL-15 through activation of mammalian target of rapamycin (mTOR) signaling, which is associated with an increased rate of glycolysis to meet higher biosynthetic demand by metabolizing glucose into lactate in a process called aerobic glycolysis. Aerobic glycolysis is needed to provide the cell with essential precursors for amino acids, lipids, and nucleotides to fuel effector function and proliferation. (C) Following IL-33 stimulation, activated ILC2s can also increase aerobic glycolysis, which is dependent on arginase-1 (Arg1) activity to metabolize extracellular l-arginine into ornithine-derived polyamines to fuel increased glycolysis (left panel). Alternatively, ILC2s take up extracellular long-chain fatty acids through an undefined transporter and utilize mitochondrial fatty acid oxidation (FAO) to fuel proliferation and effector function without the need of glucose uptake (right panel) (D) In response to IL-1β and IL-23, ILC3s increase both glucose and fatty acid metabolism and display increased mitochondrial oxygen consumption.