2. Academic Validation
  3. Sustained exposure to Helicobacter pylori induces immune tolerance by desensitizing TLR6

Sustained exposure to Helicobacter pylori induces immune tolerance by desensitizing TLR6

  • Gastric Cancer. 2024 Mar;27(2):324-342. doi: 10.1007/s10120-023-01461-7.
Xiulin Zhang 1 2,  Yang He 1 3,  Xiaolu Zhang 1,  Bo Fu 1,  Zidai Song 1,  Liang Wang 4,  Rui Fu 5,  Xuancheng Lu 6,  Jin Xing 5,  Jianyi Lv 1,  Meng Guo 1,  Xueyun Huo 1,  Xin Liu 1,  Jing Lu 1,  Xiaoyan Du 1,  Zhongming Ge 7,  Zhenwen Chen 1,  Changlong Li 8
Affiliations

Affiliations

  • 1 Department of Medical Genetics and Developmental Biology, School of Basic Medical Science, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Laboratory for Clinical Medicine, Capital Medical University, Beijing, People's Republic of China.
  • 2 State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Science, Beijing, People's Republic of China.
  • 3 School of Nursing, Dalian Medical University, Dalian, People's Republic of China.
  • 4 Peking University Ninth School of Clinical Medicine, Beijing, People's Republic of China.
  • 5 Institute for Laboratory Animal Resources, National Institutes for Food and Drug Control, Beijing, People's Republic of China.
  • 6 Laboratory Animal Center, Chinese Center for Disease Control and Prevention, Beijing, People's Republic of China.
  • 7 Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, USA.
  • 8 Department of Medical Genetics and Developmental Biology, School of Basic Medical Science, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Laboratory for Clinical Medicine, Capital Medical University, Beijing, People's Republic of China. licl@ccmu.edu.cn.
PMID: 38310631 DOI: 10.1007/s10120-023-01461-7
Abstract

Helicobacter pylori (H. pylori, Hp) has been designated a class I carcinogen and is closely associated with severe gastric diseases. During colonization in the gastric mucosa, H. pylori develops immune escape by inducing host immune tolerance. The gastric epithelium acts as the first line of defense against H. pylori, with Toll-like receptors (TLRs) in gastric epithelial cells being sensitive to H. pylori components and subsequently activating the innate immune system. However, the mechanism of immune tolerance induced by H. pylori through the TLR signalling pathway has not been fully elucidated. In this research, we detected the expression of TLRs and inflammatory cytokines in GES-1 cells upon sustained exposure to H. pylori or H. pylori lysate from 1 to 30 generations and in Mongolian gerbils infected with H. pylori for 5 to 90 weeks. We found that the levels of TLR6 and inflammatory cytokines first increased and then dropped during the course of H. pylori treatment in vitro and in vivo. The restoration of TLR6 potentiated the expression of IL-1β and IL-8 in GES-1 cells, which recruited neutrophils and reduced the colonization of H. pylori in the gastric mucosa of gerbils. Mechanistically, we found that persistent Infection with H. pylori reduces the sensitivity of TLR6 to Bacterial components and regulates the expression of inflammatory cytokines in GES-1 cells through TLR6/JNK signaling. The TLR6 Agonist obviously alleviated inflammation in vitro and in vivo. Promising results suggest that TLR6 may be a potential candidate immunotherapy drug for H. pylori Infection.

Keywords

GES-1 cells; H. pylori; Immune tolerance; Mongolian gerbils; TLR6.

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