E3 Ligase VHL Promotes Group 2 Innate Lymphoid Cell Maturation and Function via Glycolysis Inhibition and Induction of Interleukin-33 Receptor

• Published in: Immunity (Cambridge, Mass.) Vol. 48; no. 2; pp. 258 - 270.e5
• Main Authors: Li, Qian, Li, Dulei, Zhang, Xian, Wan, Qingqing, Zhang, Wen, Zheng, Mingke, Zou, Le, Elly, Chris, Lee, Jee H., Liu, Yun-Cai
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20-02-2018; Elsevier Limited
• Subjects: allergy; Animals; Bone marrow; Cell Differentiation; Clonal deletion; Cytokines; Effector cells; epigenetics; Epigenomics; Glycolysis; HIF; Hypersensitivity; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - physiology; Hypoxia-inducible factor 1a; ILC2; Immune response; Infections; Inhibition; innate lymphoid cells; Interleukin-1 Receptor-Like 1 Protein - genetics; Interleukin-33 - pharmacology; Interleukins; lung inflammation; Lungs; Lymphocytes; Lymphocytes - physiology; Lymphoid cells; Lymphoid tissue; Maturation; Metabolism; Mice; Neurons; Osteoprogenitor cells; Pyruvate kinase; Pyruvic acid; Receptors, Interleukin - physiology; Rodents; Roles; Signal Transduction; Tissues; Transcription factors; Ubiquitin; Ubiquitin-protein ligase; Ubiquitin-Protein Ligases - physiology; VHL; VHL protein; Von Hippel-Lindau Tumor Suppressor Protein - physiology; ILC2; hypoxia; HIF; glycolysis; allergy; metabolism; VHL; innate lymphoid cells; epigenetics; lung inflammation
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2017.12.013

Group 2 innate lymphoid cells (ILC2s) are a specialized subset of lymphoid effector cells that are critically involved in allergic responses; however, the mechanisms of their regulation remain unclear. We report that conditional deletion of the E3 ubiquitin ligase VHL in innate lymphoid progenitors minimally affected early-stage bone marrow ILC2s but caused a selective and intrinsic decrease in mature ILC2 numbers in peripheral non-lymphoid tissues, resulting in reduced type 2 immune responses. VHL deficiency caused the accumulation of hypoxia-inducible factor 1α (HIF1α) and attenuated interleukin-33 (IL-33) receptor ST2 expression, which was rectified by HIF1α ablation or inhibition. HIF1α-driven expression of the glycolytic enzyme pyruvate kinase M2 downmodulated ST2 expression via epigenetic modification and inhibited IL-33-induced ILC2 development. Our study indicates that the VHL-HIF-glycolysis axis is essential for the late-stage maturation and function of ILC2s via targeting IL-33-ST2 pathway.
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•VHL promotes maturation of ILC2s and lung inflammation•VHL intrinsically regulates ILC2 development•The VHL-HIF axis promotes the expression of the IL-33 receptor ST2•The PKM2-pyruvate checkpoint inhibits epigenetic modification of the ST2 gene
ILC2s are critically involved in allergic responses, but the mechanisms by which they are regulated remain unclear. Li et al. demonstrate that the VHL-HIF axis is essential for ILC2 maturation and function via inhibition of glycolysis and induction of IL-33 receptor expression. These findings have implications for identifying therapeutic targets for allergic diseases.