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

Abstract Background The role of lung group 2 innate lymphoid cell (ILC2) activation in allergic asthma is increasingly established. However, the regulatory mechanisms underlying hypoxia‐inducible factor‐1α (HIF‐1α)‐mediated glycolysis in ILC2‐mediated allergic airway inflammation remain unclear. Objective To investigate the role of the HIF‐1α/glycolysis axis in ILC2‐mediated allergic airway inflammation. Methods Glycolysis and HIF‐1α 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‐1α in mice under interleukin‐33 (IL‐33) stimulation were performed to test ILC2 responses. Conditional HIF‐1α‐deficient mice were used to confirm the specific role of HIF‐1α in ILC2‐driven airway inflammation models. Transcriptomic, metabolic, and chromatin immunoprecipitation analyses were performed to elucidate the underlying mechanism. Results HIF‐1α 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‐1α, 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‐1α inhibitor 2‐methoxyestradiol (2‐ME) abrogated inflammation by suppressing ILC2s function. Conditional HIF‐1α‐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‐1α knockout mice compared to that in their littermate controls. Chromatin immunoprecipitation results confirmed the transcriptional downregulation of glycolysis‐related genes in HIF‐1α‐knockout and 2‐DG‐treated mice. Furthermore, impaired HIF‐1α/glycolysis axis activation is correlated with downregulated ILC2 in patients with asthma. Conclusion The HIF‐1α/glycolysis axis is critical for controlling ILC2 responses in allergic airway inflammation and has potential immunotherapeutic value in asthma.