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

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

doi:10.1016/j.jcmgh.2023.10.001

Cited by 8 publications

(7 citation statements)

References 53 publications

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“…Activation of proinflammatory M1-like macrophages is associated with reduced bacterial colonization but also increased epithelial damage and gastric atrophy (44, 45) . In contrast, factors that impair macrophage activation lead to increased bacterial loads and reduced gastric atrophy (11, 46) . Our results demonstrate that impaired macrophage activation through deletion of the GR reduced gastric atrophy and PM development.…”

Section: Discussionmentioning

confidence: 99%

“…Numerous studies have demonstrated that macrophages are essential during the anti- Helicobacter immune response. Macrophages control H. pylori gastric burden, and impaired macrophage function leads to higher H. pylori bacterial loads (11) . However, macrophages also promote gastric atrophy progression and macrophage depletion reduces H. pylori -associated gastric atrophy (12) .…”

Section: Introductionmentioning

confidence: 99%

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Endogenous glucocorticoids are required for normal macrophage activation and gastricHelicobacter pyloriimmunity

Khadka,

Dziadowicz,

et al. 2024

Preprint

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Glucocorticoids are steroid hormones well-known for their potent anti-inflammatory effects. However, their immunomodulatory properties are multifaceted. Increasing evidence suggests that glucocorticoid signaling promotes effective immunity and that disruption of glucocorticoid signaling impairs immune function. In this study, we conditionally deleted the glucocorticoid receptor (GR) in the myeloid lineage using the LysM-Cre driver (myGRKO). We examined the impact on macrophage activation and gastric immune responses to Helicobacter pylori, the best-known risk factor of gastric cancer. Our results indicate that compared to WT, GRKO macrophages exhibited higher expression of proinflammatory genes in steroid-free conditions. However, when challenged in vivo, GRKO macrophages exhibited aberrant chromatin landscapes and impaired proinflammatory gene expression profiles. Moreover, gastric colonization with Helicobacter revealed impaired gastric immune responses and reduced T cell recruitment in myGRKO mice. As a result, myGRKO mice were protected from atrophic gastritis and pyloric metaplasia development. These results demonstrate a dual role for glucocorticoid signaling in preparing macrophages to respond to bacterial infection but limiting their pathogenic activation. In addition, our results support that macrophages are critical for gastric anti-Helicobacter immunity.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Endogenous glucocorticoids are required for normal macrophage activation and gastricHelicobacter pyloriimmunity

Khadka,

Dziadowicz,

et al. 2024

Preprint

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“…Similarly, polymorphisms resulting in higher levels of the proinflammatory cytokines IL1B or TNF and lower levels of the anti-inflammatory cytokine IL10 are associated with increases in HP-related gastric cancer (6,7) . In contrast, multiple immune-deficient mouse models are protected from the gastric pathologies associated with Helicobacter infection (8)(9)(10) .…”

Section: Introductionmentioning

confidence: 99%

Comparison of gastric inflammation and metaplasia induced byHelicobacter pyloriorHelicobacter feliscolonization in mice

Druffner,

Venkateshwaraprabu,

Khadka

et al. 2023

Preprint

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BackgroundGastric cancer is the fifth most diagnosed cancer in the world. Infection by the bacteriaHelicobacter pylori(HP) is associated with approximately 75% of gastric cancer cases. HP infection induces chronic gastric inflammation, damaging the stomach and fostering carcinogenesis. Most mechanistic studies onHelicobacter-induced gastric cancer initiation are performed in mice and utilize either mouse-adapted strains of HP or the natural mouse pathogenHelicobacter felis(HF). Each of these infection models is associated with strengths and weaknesses. Here, we identified the differences in immunogenicity and gastric pathological changes associated with HP and HF infection in mice.Material and MethodsPMSS1 HP strain or with the CS1 HF strain were co-cultured with mouse peritoneal macrophages to assess their immunostimulatory effects. C57BL/6J mice were infected with HP or HF, and gastric inflammation, atrophy, and metaplasia development were assessed 2 months post-infection.ResultsHP and HF induced similar cytokine production from cultured mouse peritoneal macrophages. HP-infected mice caused modest inflammation within both the gastric corpus and antrum and did not induce significant atrophy within the gastric corpus. In contrast, HF induced significant inflammation throughout the gastric corpus and antrum. Moreover, HF infection was associated with significant atrophy of the chief and parietal cell compartments and induced expression of pyloric metaplasia markers.ConclusionsHP is poorly immunogenic compared to HF. HF induces dramatic CD4+ T cell activation, which is associated with increased gastric cancer risk in humans. Thus, HP studies in mice are better suited for studies on colonization, while HF is more strongly suited for pathogenesis and cancer initiation studies.

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“…Among the key innate immune players, macrophages have emerged as pivotal early responders during H pylori infection. In this issue of Cellular and Molecular Gastroenterology and Hepatology , Modi et al 5 identified a role for a transcriptional regulatory, known as bromodomain-containing protein 4 (BRD4), in macrophage killing of H pylori. BRD4 has been identified as a critical modulator of proinflammatory responses in myeloid cell lineages, including macrophages, in the context of bacterial infections.…”

mentioning

confidence: 99%

“… 6 The study used LyzM Cre/Cre conditional BRD4 LoxP/LoxP knockout (KO) mice, which lack BRD4 specifically in myeloid cells, to show that BRD4 expression is important for regulating glycolysis-dependent nitric oxide production in macrophages in response to H pylori infection. 5 …”

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confidence: 99%

BRD4 Empowers Macrophages to Fight Helicobacter pylori

Hoft,

DiPaolo

2023

Cellular and Molecular Gastroenterology and Hepatology

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

Cited by 8 publications

References 53 publications

Endogenous glucocorticoids are required for normal macrophage activation and gastricHelicobacter pyloriimmunity

Endogenous glucocorticoids are required for normal macrophage activation and gastricHelicobacter pyloriimmunity

Comparison of gastric inflammation and metaplasia induced byHelicobacter pyloriorHelicobacter feliscolonization in mice

BRD4 Empowers Macrophages to Fight Helicobacter pylori

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