Critical role of fatty acid metabolism in ILC2-mediated barrier protection during malnutrition and helminth infection

Abstract

Belkaid et al. show that type 2 innate lymphoid cells rely predominately on fatty acid metabolism during helminth infection and malnutrition.

Cellular and molecular regulation of innate inflammatory responses

“…148 Whereas ILC1s and ILC3s are essential to host defense against infection by viruses, intracellular bacteria and parasites, ILC2s potently drive type 2 inflammation and mediate allergic inflammation, tissue repair and anti-helminth innate immunity. [149][150][151][152][153] A novel population of IL-25-responsive inflammatory ILC2 (iILC2) could develop into IL-33-responsive natural ILC2 (nILC2)-like cells and contribute to immunity to both helminths and fungi. 154,155 Inflammatory cytokines such as IL-1 and IFN, 156,157 and crosstalk with stromal cells, epithelial cells and various immune cells such as DC, 158 T cells 159 and B cells 160,161 are important for regulation of ILC function and plasticity at the crossroad of homeostasis and inflammation.…”

Innate Lymphoid Cell Immunometabolism

“…Other studies suggest that intestinal ILC2s express a genetic signature enriched in genes involved in fatty acid metabolism[54], and intestinal ILC2s as well as ILC3s have been shown to uptake extracellular fatty acids from their environment during homeostasis[55]. Inhibition of systemic fatty acid oxidation (FAO) by treatment of etomoxir in vivo , but not systemic inhibition of glycolysis, reduced intestinal ILC2 accumulation and production of IL-13 and IL-5 in response to helminth infection[55].…”

“…Inhibition of systemic fatty acid oxidation (FAO) by treatment of etomoxir in vivo , but not systemic inhibition of glycolysis, reduced intestinal ILC2 accumulation and production of IL-13 and IL-5 in response to helminth infection[55]. These results suggest that ILC2s may be metabolically distinct from other lymphocytes in that they could preferentially use lipid-fueled FAO to support their proliferation and effector functions during pathogen-induced inflammation (Fig.…”

“…However, whether this mechanism is ILC2-intrinsic or specific to intestinal ILC2s is still unclear. Although ILC2s and ILC3s have increased rates of extracellular fatty acid uptake compared to regulatory T cells in the small intestine, blockade of FAO by etomoxir does not perturb ILC2 homeostasis in vivo [55]. Therefore, future work will be needed to uncover the specific metabolic pathways that are utilized by ILC2s and ILC3s during activation and homeostasis.…”

“…Dietary nutrient deficiencies, such as Vitamin A deficiency, leads to a loss of ILC3s in the gut[79], while ILC2 number and effector function are enhanced by increased FAO and acquisition of long-chained fatty acids[55]. Dietary nutrient oversupply of fat, which leads to obesity, results in the hypertrophy of adipocytes, limiting their nutrient and oxygen availability and resulting in a sustained stress response in both adipocytes and stromal cells[80–82].…”