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Whitney, Annette E.; Emory, Theresa S.; Marty, Aileen M.; O’Shea, Patricia; Newman, Gale W.; Gold, Benjamin D.

doi:10.1023/a:1005551903029

“…During H. pylori infection, macrophages are recruited to the gastric mucosa, where they contribute to the production of pro-inflammatory cytokines and chemokines [10], [11], [12], [13], [14], [15]. In addition, a recent study showed that liposome-mediated depletion of macrophages reduced gastric pathology in H. pylori -infected mice [16].…”

Section: Introductionmentioning

confidence: 99%

Enhanced M1 Macrophage Polarization in Human Helicobacter pylori-Associated Atrophic Gastritis and in Vaccinated Mice

Quiding‐Järbrink

¹

,

Raghavan

²

,

Sundquist

³

2010

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BackgroundInfection with Helicobacter pylori triggers a chronic gastric inflammation that can progress to atrophy and gastric adenocarcinoma. Polarization of macrophages is a characteristic of both cancer and infection, and may promote progression or resolution of disease. However, the role of macrophages and their polarization during H. pylori infection has not been well defined.Methodology/Principal FindingsBy using a mouse model of infection and gastric biopsies from 29 individuals, we have analyzed macrophage recruitment and polarization during H. pylori infection by flow cytometry and real-time PCR. We found a sequential recruitment of neutrophils, eosinophils and macrophages to the gastric mucosa of infected mice. Gene expression analysis of stomach tissue and sorted macrophages revealed that gastric macrophages were polarized to M1 after H. pylori infection, and this process was substantially accelerated by prior vaccination. Human H. pylori infection was characterized by a mixed M1/M2 polarization of macrophages. However, in H. pylori-associated atrophic gastritis, the expression of inducible nitric oxide synthase was markedly increased compared to uncomplicated gastritis, indicative of an enhanced M1 macrophage polarization in this pre-malignant lesion.Conclusions/SignificanceThese results show that vaccination of mice against H. pylori amplifies M1 polarization of gastric macrophages, and that a similar enhanced M1 polarization is present in human H. pylori-induced atrophic gastritis.

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“…Besides, the H. pylori -induced gastric epithelial damage enables the bacteria to enter lamina propria and encounter macrophages7. Macrophages infiltration into gastric mucosa is detected in the H. pylori -infected patients8, which can function to capture the bacteria7. Both M1 and M2 macrophages are detected in gastric biopsy specimens isolated from H. pylori -infected patients, indicating the importance of macrophages in host defense against H. pylori 910.…”

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confidence: 99%

Suppression of cell division-associated genes by Helicobacter pylori attenuates proliferation of RAW264.7 monocytic macrophage cells

Tan¹,

Looi

²

,

Fernandez³

et al. 2015

Sci Rep

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Helicobacter pylori at multiplicity of infection (MOI ≥ 50) have been shown to cause apoptosis in RAW264.7 monocytic macrophage cells. Because chronic gastric infection by H. pylori results in the persistence of macrophages in the host’s gut, it is likely that H. pylori is present at low to moderate, rather than high numbers in the infected host. At present, the effect of low-MOI H. pylori infection on macrophage has not been fully elucidated. In this study, we investigated the genome-wide transcriptional regulation of H. pylori-infected RAW264.7 cells at MOI 1, 5 and 10 in the absence of cellular apoptosis. Microarray data revealed up- and down-regulation of 1341 and 1591 genes, respectively. The expression of genes encoding for DNA replication and cell cycle-associated molecules, including Aurora-B kinase (AurkB) were down-regulated. Immunoblot analysis verified the decreased expression of AurkB and downstream phosphorylation of Cdk1 caused by H. pylori infection. Consistently, we observed that H. pylori infection inhibited cell proliferation and progression through the G1/S and G2/M checkpoints. In summary, we suggest that H. pylori disrupts expression of cell cycle-associated genes, thereby impeding proliferation of RAW264.7 cells, and such disruption may be an immunoevasive strategy utilized by H. pylori.

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“…Gastric inflammatory protein levels were quantified in male mice, including macrophage-associated proteins given histiocytic activation occurs in H. pylori infection ( 32 , 35 , 36 ). Gastric protein levels of GM-CSF and M-CSF, which regulate macrophage differentiation, MCP-1, a key monocyte chemoattractant, and MIP-1α and MIP-2, inflammatory proteins produced by macrophages, were decreased in male mice coinfected with C. acnes followed by H. pylori compared to H. pylori monoinfection.…”

Section: Discussionmentioning

confidence: 99%

Gastric coinfection with thiopeptide-positive Cutibacterium acnes decreases FOXM1 and pro-inflammatory biomarker expression in a murine model of Helicobacter pylori -induced gastric cancer

Lunger,

Shen,

Holcombe

et al. 2024

Microbiol Spectr

0

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Helicobacter pylori ( H. pylori ) causes a cascade from gastritis to gastric neoplasia. During the chronic stages, the oncogenic transcription factor forkhead box protein M1 ( FOXM1 ) becomes increasingly expressed. Given certain strains of the gastric commensal Cutibacterium acnes ( C. acnes ) produce thiopeptides that directly inhibit FOXM1, we hypothesized that coinfection with thiopeptide-positive C. acnes would decrease Foxm1 expression and alter H. pylori -induced pathogenesis. C. acnes was isolated from 31% of gastric biopsies from Nicaraguan patients, and thiopeptide-positive strains were identified by whole genome sequencing. Germ-free INS-GAS mice were inoculated with thiopeptide-positive C. acnes , H. pylori SS1, H. pylori 1 week before C. acnes , C. acnes 2 weeks before H. pylori , or no bacteria. At 17 weeks post-infection, males dosed with C. acnes followed by H. pylori exhibited increased inflammation scores by histopathology; however, males dosed with H. pylori followed by C. acnes exhibited reduced gastric Foxm1 , pro-inflammatory cytokine ( Il-1β , Ifn-γ , Tnf-α , Il-17a , and iNOS ), regulatory cytokine ( Foxp3 ) gene expression, pro-inflammatory IgG2a antibodies, and gastric lymph node RORγT expression compared to H. pylori- monoinfected mice. Male mice coinfected with C. acnes followed by H. pylori exhibited reduced gastric inflammatory markers (IL-17, IL-10, GM-CSF, M-CSF, MCP-1, MIP-1α, MIP-2, RANTES, and VEGF) by cytokine array analysis and reduced H. pylori gastric colonization. These data show that thiopeptide-positive C. acnes exhibited anti-inflammatory and anti-FOXM1 properties in the context of H. pylori gastritis. IMPORTANCE H. pylori infects half of the world population and is the leading cause of gastric cancer. We previously demonstrated that gastric cancer risk is associated with gastric microbiota. Specifically, gastric urease-positive Staphylococcus epidermidis and Streptococcus salivarius had contrasting effects on H. pylori -associated gastric pathology and immune responses in germ-free INS-GAS mice. As gastritis progresses to gastric cancer, the oncogenic transcription factor Foxm1 becomes increasingly expressed. In this study, we evaluated the gastric commensal C. acnes , certain strains of which produce thiopeptides that directly inhibit FOXM1. Thiopeptide-positive C. acnes was isolated from Nicaraguan patient gastric biopsies and inoculated into germ-free INS-GAS mice with H. pylori . We, therefore, asked whether coinfection with C. acnes expressing thiopeptide and H. pylori would decrease gastric Foxm1 expression and pro-inflammatory cytokine mRNA and protein levels. Our study supports the growing literature that specific non- H . pylori gastric bacteria affect inflammatory and cancer biomarkers in H. pylori pathogenesis.

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Cited by 20 publications

References 21 publications

Enhanced M1 Macrophage Polarization in Human Helicobacter pylori-Associated Atrophic Gastritis and in Vaccinated Mice

Enhanced M1 Macrophage Polarization in Human Helicobacter pylori-Associated Atrophic Gastritis and in Vaccinated Mice

Suppression of cell division-associated genes by Helicobacter pylori attenuates proliferation of RAW264.7 monocytic macrophage cells

Gastric coinfection with thiopeptide-positive Cutibacterium acnes decreases FOXM1 and pro-inflammatory biomarker expression in a murine model of Helicobacter pylori -induced gastric cancer

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