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Open AccessArticle

Dysregulated Immune Responses by ASK1 Deficiency Alter Epithelial Progenitor Cell Fate and Accelerate Metaplasia Development during H. pylori Infection

1
Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan
2
Division of Advanced Genome Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
3
Department of Gastroenterology, The Institute for Adult Diseases, Asahi-Life Foundation, Tokyo 103-0002, Japan
4
Department of Gastroenterology, Yokohama City University 3-9 Fukuura, Kanazawa-ku, Yokohama 236-0004, Japan
*
Authors to whom correspondence should be addressed.
Microorganisms 2020, 8(12), 1995; https://doi.org/10.3390/microorganisms8121995
Received: 16 November 2020 / Revised: 11 December 2020 / Accepted: 11 December 2020 / Published: 14 December 2020
(This article belongs to the Special Issue Helicobacter pylori and Gastric Carcinogenesis)
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. View Full-Text
Keywords: Helicobacter pylori; ASK1; gastritis; metaplasia; progenitors Helicobacter pylori; ASK1; gastritis; metaplasia; progenitors
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MDPI and ACS Style

Hayakawa, Y.; Hirata, Y.; Hata, M.; Tsuboi, M.; Oya, Y.; Kurokawa, K.; Abe, S.; Arai, J.; Suzuki, N.; Nakagawa, H.; Fujiwara, H.; Tateishi, K.; Maeda, S.; Koike, K. Dysregulated Immune Responses by ASK1 Deficiency Alter Epithelial Progenitor Cell Fate and Accelerate Metaplasia Development during H. pylori Infection. Microorganisms 2020, 8, 1995. https://doi.org/10.3390/microorganisms8121995

AMA Style

Hayakawa Y, Hirata Y, Hata M, Tsuboi M, Oya Y, Kurokawa K, Abe S, Arai J, Suzuki N, Nakagawa H, Fujiwara H, Tateishi K, Maeda S, Koike K. Dysregulated Immune Responses by ASK1 Deficiency Alter Epithelial Progenitor Cell Fate and Accelerate Metaplasia Development during H. pylori Infection. Microorganisms. 2020; 8(12):1995. https://doi.org/10.3390/microorganisms8121995

Chicago/Turabian Style

Hayakawa, Yoku; Hirata, Yoshihiro; Hata, Masahiro; Tsuboi, Mayo; Oya, Yukiko; Kurokawa, Ken; Abe, Sohei; Arai, Junya; Suzuki, Nobumi; Nakagawa, Hayato; Fujiwara, Hiroaki; Tateishi, Keisuke; Maeda, Shin; Koike, Kazuhiko. 2020. "Dysregulated Immune Responses by ASK1 Deficiency Alter Epithelial Progenitor Cell Fate and Accelerate Metaplasia Development during H. pylori Infection" Microorganisms 8, no. 12: 1995. https://doi.org/10.3390/microorganisms8121995

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