title: Helicobacter pylori infection inhibits phagocyte clearance of apoptotic gastric epithelial cells.
abstract: Increased apoptotic death of gastric epithelial cells is a hallmark of Helicobacter pylori infection, and altered epithelial cell turnover is an important contributor to gastric carcinogenesis. To address the fate of apoptotic gastric epithelial cells and their role in H. pylori mucosal disease, we investigated phagocyte clearance of apoptotic gastric epithelial cells in H. pylori infection. Human gastric mononuclear phagocytes were analyzed for their ability to take up apoptotic epithelial cells (AECs) in vivo using immunofluorescence analysis. We then used primary human gastric epithelial cells induced to undergo apoptosis by exposure to live H. pylori to study apoptotic cell uptake by autologous monocyte-derived macrophages. We show that HLA-DR(+) mononuclear phagocytes in human gastric mucosa contain cytokeratin-positive and TUNEL-positive AEC material, indicating that gastric phagocytes are involved in AEC clearance. We further show that H. pylori both increased apoptosis in primary gastric epithelial cells and decreased phagocytosis of the AECs by autologous monocyte-derived macrophages. Reduced macrophage clearance of apoptotic cells was mediated in part by H. pylori-induced macrophage TNF-α, which was expressed at higher levels in H. pylori-infected, compared with uninfected, gastric mucosa. Importantly, we show that H. pylori-infected gastric mucosa contained significantly higher numbers of AECs and higher levels of nonphagocytosed TUNEL-positive apoptotic material, consistent with a defect in apoptotic cell clearance. Thus, as shown in other autoimmune and chronic inflammatory diseases, insufficient phagocyte clearance may contribute to the chronic and self-perpetuating inflammation in human H. pylori infection.
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Diane
authors.initials: D
authors.lastname: Bimczok
authors.forename: Lesley E
authors.initials: LE
authors.lastname: Smythies
authors.forename: Ken B
authors.initials: KB
authors.lastname: Waites
authors.forename: Jayleen M
authors.initials: JM
authors.lastname: Grams
authors.forename: Richard D
authors.initials: RD
authors.lastname: Stahl
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mannon
authors.forename: Shajan
authors.initials: S
authors.lastname: Peter
authors.forename: C Mel
authors.initials: CM
authors.lastname: Wilcox
authors.forename: Paul R
authors.initials: PR
authors.lastname: Harris
authors.forename: Soumita
authors.initials: S
authors.lastname: Das
authors.forename: Peter B
authors.initials: PB
authors.lastname: Ernst
authors.forename: Phillip D
authors.initials: PD
authors.lastname: Smith
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D004847:Epithelial Cells / Q000473:pathology*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005753:Gastric Mucosa / Q000166:cytology / Q000276:immunology; D016481:Helicobacter Infections / Q000276:immunology* / Q000473:pathology; D016480:Helicobacter pylori; D006801:Humans; D020287:In Situ Nick-End Labeling; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D010587:Phagocytosis; D020133:Reverse Transcriptase Polymerase Chain Reaction