Innate Lymphoid Cell Immunometabolism

Abstract

Innate lymphoid cells (ILCs) are tissue-resident "first responders" of the immune system that function to protect epithelial barriers against pathogens and maintain tissue homeostasis. However, because ILCs are finely tuned to perturbations within tissue microenvironments, they can also contribute to host pathology when upstream activating signals are 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 brief review, we summarize recent studies that demonstrate the ability of ILCs to influence tissue and systemic metabolism, as well as how ILC biology can be regulated by environmental changes in host metabolism. We also highlight studies showing 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 immunometabolism.

Keywords: innate lymphoid cells; metabolism.

Figure 1. Metabolic Pathways utilized by ILCs during homeostasis and activation

(A) Resting 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 triphpsohate (ATP). However, during inflammation ILCs respond to increased levels of proinflammtory cytokines that cause their activation and concomitant changes in cellular metabolism. (B) NK cells respond to heighten levels of the cytokines IL-12, IL-18 and IL-15 through activation of 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. (D) During helminth infection in vivo, ILC2s in the intestine do not require glucose uptake to fuel their effector functions. Rather, 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.