Abstract
The mechanism of H. pylori-induced atrophy and metaplasia has not been fully understood. Here, we demonstrate the novel role of Apoptosis signal-regulating kinase 1 (ASK1) and downstream MAPKs as a regulator of host immune responses and epithelial maintenance against H. pylori infection. ASK1 gene deficiency resulted in enhanced inflammation with numerous inflammatory cells including Gr-1+CD11b+ myeloid-derived suppressor cells (MDSCs) recruited into the infected stomach. Increase of IL-1β release from apoptotic macrophages and enhancement of TH1-polarized immune responses caused STAT1 and NF-κB activation in epithelial cells in ASK1 knockout mice. Dysregulated immune and epithelial activation in ASK1 knockout mice led to dramatic expansion of gastric progenitor cells and massive metaplasia development. Bone marrow transplantation experiments revealed that ASK1 in inflammatory cells is critical for inducing immune disorder and metaplastic changes in epithelium, while ASK1 in epithelial cells regulates cell proliferation in stem/progenitor zone without changes in inflammation and differentiation. These results suggest that H. pylori-induced immune cells may regulate epithelial homeostasis and cell fate as an inflammatory niche via ASK1 signaling.
Highlights
Helicobacter pylori (H. pylori) is associated with various human gastric diseases, including gastric ulcer, chronic gastritis, and gastric neoplasia [1,2]
In AGS cells, H. pylori TN2 strain and PMSS-1 could increase the phosphorylated level of Apoptosis signal-regulating kinase 1 (ASK1), while Sydney strain 1 (SS-1) did not, suggesting that TFSS is necessary for ASK1 activation in gastric epithelial cells (Figure 1A)
We infected WT and ASK1−/− mice with SS-1 and PMSS-1 for up to 3 months and examined protein expression in the stomachs. Both infected stomachs showed increased level of ASK1 phosphorylation compared to noninfected stomach, and PMSS-1-infected stomach displayed greater level of phosphorylated ASK1 than SS-1-infected stomach (Figure 1B). These results indicate that PMSS-1 activates ASK1 in gastric epithelium via phosphorylation more strongly than SS-1
Summary
Helicobacter pylori (H. pylori) is associated with various human gastric diseases, including gastric ulcer, chronic gastritis, and gastric neoplasia [1,2]. ASK1 regulates bacterial killing ability in macrophages and controls their cell fate, which affects systemic immune responses and carcinogenesis in mice [37] It has not been fully elucidated whether ASK1 plays a role in H. pylori-induced host immune responses and affects epithelial differentiation. ASK1 in inflammatory cells plays a critical role for preventing gastric atrophy and metaplastic changes through IL-1β release, TH1-polarized immune responses, and the recruitment of Gr-1+CD11b+ myeloid-derived suppressor cells (MDSCs), while ASK1 in epithelial cells regulates stem/progenitor cell proliferation. Abnormal inflammatory responses that were caused by ASK1 deficiency resulted in altered distribution of gastric facultative progenitor cells in metaplastic lesions These results highlight the novel role of ASK1 in the interaction between host immune responses and epithelial homeostasis during H. pylori infection
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