Blocking the HIF-1α/glycolysis axis inhibits allergic airway inflammation by reducing ILC2 metabolism and function

BackgroundThe role of lung group 2 innate lymphoid cell (ILC2) activation in allergic asthma is increasingly established. However, the regulatory mechanisms underlying hypoxia-inducible factor-1 alpha (HIF-1 alpha)-mediated glycolysis in ILC2-mediated allergic airway inflammation remain unclear.ObjectiveTo investigate the role of the HIF-1 alpha/glycolysis axis in ILC2-mediated allergic airway inflammation.MethodsGlycolysis and HIF-1 alpha inhibitors were used to identify their effect on the function and glucose metabolism of mouse and human ILC2s in vivo and vitro. Blocking glycolysis and HIF-1 alpha in mice under interleukin-33 (IL-33) stimulation were performed to test ILC2 responses. Conditional HIF-1 alpha-deficient mice were used to confirm the specific role of HIF-1 alpha in ILC2-driven airway inflammation models. Transcriptomic, metabolic, and chromatin immunoprecipitation analyses were performed to elucidate the underlying mechanism.ResultsHIF-1 alpha is involved in ILC2 metabolism and is crucial in allergic airway inflammation. Single-cell sequencing data analysis and qPCR confirmation revealed a significant upregulation of glycolysis-related genes, particularly HIF-1 alpha, in murine lung ILC2s after IL-33 intranasal administration or injection. Treatment with the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) and the HIF-1 alpha inhibitor 2-methoxyestradiol (2-ME) abrogated inflammation by suppressing ILC2s function. Conditional HIF-1 alpha-deficient mice showed reduced ILC2 response and airway inflammation induced upon IL-33 or house dust mite (HDM) stimulation. Transcriptome and metabolic analyses revealed significantly impaired glycolysis in lung ILC2s in conditional HIF-1 alpha knockout mice compared to that in their littermate controls. Chromatin immunoprecipitation results confirmed the transcriptional downregulation of glycolysis-related genes in HIF-1 alpha-knockout and 2-DG-treated mice. Furthermore, impaired HIF-1 alpha/glycolysis axis activation is correlated with downregulated ILC2 in patients with asthma.ConclusionThe HIF-1 alpha/glycolysis axis is critical for controlling ILC2 responses in allergic airway inflammation and has potential immunotherapeutic value in asthma.