The E3 ligase VHL controls alveolar macrophage function via metabolic-epigenetic regulation

Wen Zhang, Qian Li, Dulei Li, Jia Li, Daisuke Aki, Yun Cai Liu

Research output: Contribution to journalArticle

Abstract

Metabolic pathways such as glycolysis or oxidative phosphorylation play a key role in regulating macrophage function during inflammation and tissue repair. However, how exactly the VHL-HIF-glycolysis axis is involved in the function of tissue-resident macrophages remains unclear. Here we demonstrate that loss of VHL in myeloid cells resulted in attenuated pulmonary type 2 and fibrotic responses, accompanied by reduced eosinophil infiltration, decreased IL-5 and IL-13 concentrations, and ameliorated fiber deposition upon challenge. VHL deficiency uplifted glycolytic metabolism, decreased respiratory capacity, and reduced osteopontin expression in alveolar macrophages, which impaired the function of type 2 innate lymphoid cells but was significantly reversed by HIF1α inhibition or ablation. The up-regulated glycolysis altered the epigenetic modification of osteopontin gene, with the metabolic intermediate 3-phosphoglyceric acid as a key checkpoint controller. Thus, our results indicate that VHL acts as a crucial regulatory factor in lung inflammation and fibrosis by regulating alveolar macrophages.

Original languageEnglish
Pages (from-to)3180-3193
Number of pages14
JournalJournal of Experimental Medicine
Volume215
Issue number12
DOIs
Publication statusPublished - 2018 Dec 1
Externally publishedYes

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Ubiquitin-Protein Ligases
Alveolar Macrophages
Glycolysis
Epigenomics
Osteopontin
Macrophages
Interleukin-13
Oxidative Phosphorylation
Interleukin-5
Myeloid Cells
Metabolic Networks and Pathways
Eosinophils
Pneumonia
Fibrosis
Lymphocytes
Inflammation
Lung
Acids
Genes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

The E3 ligase VHL controls alveolar macrophage function via metabolic-epigenetic regulation. / Zhang, Wen; Li, Qian; Li, Dulei; Li, Jia; Aki, Daisuke; Liu, Yun Cai.

In: Journal of Experimental Medicine, Vol. 215, No. 12, 01.12.2018, p. 3180-3193.

Research output: Contribution to journalArticle

Zhang, Wen ; Li, Qian ; Li, Dulei ; Li, Jia ; Aki, Daisuke ; Liu, Yun Cai. / The E3 ligase VHL controls alveolar macrophage function via metabolic-epigenetic regulation. In: Journal of Experimental Medicine. 2018 ; Vol. 215, No. 12. pp. 3180-3193.
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