BRD4 Regulates Glycolysis-Dependent Nos2 Expression in Macrophages Upon H pylori Infection

Nikita Modi, Yanheng Chen, Xingchen Dong, Xiangming Hu, Gee W. Lau, Keith T. Wilson, Richard M. Peek, Lin Feng Chen

Research output: Contribution to journalArticlepeer-review


Background & Aims: Metabolic reprogramming is essential for the activation and functions of macrophages, including bacterial killing and cytokine production. Bromodomain-containing protein 4 (BRD4) has emerged as a critical regulator of innate immune response. However, the potential role of BRD4 in the metabolic reprogramming of macrophage activation upon Helicobacter pylori infection remains unclear. Methods: Bone marrow–derived macrophages (BMDMs) from wild-type (WT) and Brd4-myeloid deletion conditional knockout (Brd4-CKO) mice were infected with H pylori. RNA sequencing was performed to evaluate the differential gene expression between WT and Brd4-deficient BMDMs upon infection. An in vivo model of H pylori infection using WT and Brd4-CKO mice was used to confirm the role of BRD4 in innate immune response to infection. Results: Depletion of Brd4 in BMDMs showed impaired H pylori–induced glycolysis. In addition, H pylori–induced expression of glycolytic genes, including Slc2a1 and Hk2, was decreased in Brd4-deficient BMDMs. BRD4 was recruited to the promoters of Slc2a1 and Hk2 via hypoxia-inducible factor-1α, facilitating their expression. BRD4-mediated glycolysis stabilized H pylori–induced nitric oxide synthase (Nos2) messenger RNA to produce nitric oxide. The NO-mediated killing of H pylori decreased in Brd4-deficient BMDMs, which was rescued by pyruvate. Furthermore, Brd4-CKO mice infected with H pylori showed reduced gastric inflammation and increased H pylori colonization with reduced inducible NO synthase expression in gastric macrophages. Conclusions: Our study identified BRD4 as a key regulator of hypoxia-inducible factor-1α–dependent glycolysis and macrophage activation. Furthermore, we show a novel regulatory role of BRD4 in innate immunity through glycolysis to stabilize Nos2 messenger RNA for NO production to eliminate H pylori infection.

Original languageEnglish (US)
Pages (from-to)292-308.e1
Issue number2
StatePublished - Jan 2024


  • BRD4
  • Glycolysis
  • H pylori
  • HIF-1α
  • iNOS

ASJC Scopus subject areas

  • Gastroenterology
  • Hepatology


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