Dysregulated immune responses by ask1 deficiency alter epithelial progenitor cell fate and accelerate metaplasia development during h. Pylori infection

Yoku Hayakawa, Yoshihiro Hirata, Masahiro Hata, Mayo Tsuboi, Yukiko Oya, Ken Kurokawa, Sohei Abe, Junya Arai, Nobumi Suzuki, Hayato Nakagawa, Hiroaki Fujiwara, Keisuke Tateishi, Shin Maeda, Kazuhiko Koike

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number1995
Pages (from-to)1-20
Number of pages20
JournalMicroorganisms
Volume8
Issue number12
DOIs
Publication statusPublished - Dec 2020

Keywords

  • ASK1
  • Gastritis
  • Helicobacter pylori
  • Metaplasia
  • Progenitors

ASJC Scopus subject areas

  • Microbiology
  • Virology
  • Microbiology (medical)

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