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

Xiaogang Zhang; Jingping Liu; Xinyao Li; Guilang Zheng; Tianci Wang; Hengbiao Sun; Zhengcong Huang; Junyu He; Ju Qiu; Zhibin Zhao; Yuxiong Guo; Yumei He

doi:10.1111/all.16361

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

Allergy. 2024 Oct 27. doi: 10.1111/all.16361. Online ahead of print.

Authors

Xiaogang Zhang¹, Jingping Liu², Xinyao Li³, Guilang Zheng⁴, Tianci Wang³, Hengbiao Sun², Zhengcong Huang³, Junyu He³, Ju Qiu⁵, Zhibin Zhao⁶, Yuxiong Guo⁴, Yumei He^{1

2

3}

Affiliations

¹ Pediatric Intensive Care Unit, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences); Department of Immunology, School of Basic Medical Sciences; Department of Clinical Laboratory, The Third Affiliated Hospital of Southern Medical University, Southern Medical University, Guangzhou, China.
² Department of Clinical Laboratory, The Third Affiliated Hospital, Southern Medical University, Guangzhou, China.
³ Department of Immunology; Guangdong Provincial Key Laboratory of Single Cell Technology and Application, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
⁴ Pediatric Intensive Care Unit, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University; Guangdong Provincial Cardiovascular Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China.
⁵ CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, China.
⁶ Medical Research Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China.

PMID: 39462230
DOI: 10.1111/all.16361

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.

Keywords: HIF‐1α; allergic lung inflammation; asthma; glycolysis; group 2 innate lymphoid cells.

Abstract

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