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The TLR/MyD88 signalling cascade in inflammation and gastric cancer: the immune regulatory network of Helicobacter pylori

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Abstract

Helicobacter pylori-induced chronic gastritis represents a well-established risk factor for gastric cancer (GC). However, the mechanism by which chronic inflammation caused by H. pylori induces the development of GC is unclear. H. pylori can influence host cell signalling pathways to induce gastric disease development and mediate cancer promotion and progression. Toll-like receptors (TLRs), as pattern recognition receptors (PRRs), play a key role in the gastrointestinal innate immune response, and their signalling has been implicated in the pathogenesis of an increasing number of inflammation-associated cancers. The core adapter myeloid differentiation factor-88 (MyD88) is shared by most TLRs and functions primarily in H. pylori-triggered innate immune signalling. MyD88 is envisioned as a potential target for the regulation of immune responses and is involved in the regulation of tumourigenesis in a variety of cancer models. In recent years, the TLR/MyD88 signalling pathway has received increasing attention for its role in regulating innate and adaptive immune responses, inducing inflammatory activation and promoting tumour formation. In addition, TLR/MyD88 signalling can manipulate the expression of infiltrating immune cells and various cytokines in the tumour microenvironment (TME). In this review, we discuss the pathogenetic regulatory mechanisms of the TLR/MyD88 signalling cascade pathway and its downstream molecules in H. pylori infection-induced-associated GC. The focus is to elucidate the immunomolecular mechanisms of pathogen recognition and innate immune system activation of H. pylori in the TME of inflammation-associated GC. Ultimately, this study will provide insight into the mechanism of H. pylori-induced chronic inflammation-induced GC development and provide thoughts for GC prevention and treatment strategies.

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Abbreviations

APC:

Antigen-presenting cell

ATRA:

all-trans retinoic acid

BMDC:

Bone marrow‐derived cell

BMDM:

Bone marrow‐derived macrophage

Cag:

Cytotoxin-related gene

CCRL:

C-C motif chemokine receptor-like

cDC:

Conventional DC

COX:

Cyclooxygenase

CTL:

Cytotoxic T lymphocyte

CXCL:

Chemokine (CXC motif) ligand

DAMP:

Damage-associated molecular pattern

DC:

Dendritic cell

NKG2D:

Natural killer group2 member

NKG2DL:

Natural killer group2 member ligand

GC:

Gastric cancer

GM-CSF::

Granulocyte macrophage–colony-stimulating factor

HKHP:

Thermal killing of Helicobacter pylori

HMGB:

High-mobility group box

Hop:

Toxicity-associated adhesin

HP-NAP:

Helicobacter pylori Neutrophil-activating protein

H. pylori:

Helicobacter pylori

IFN:

Interferon

IL:

Interleukin

IRF:

IFN regulatory factor

JAK:

Janus kinase

LPS:

Lipopolysaccharide

MAP:

Mitogen-activated protein

miRNA:

MicroRNA

MNC:

Monocyte

MyD88:

Myeloid differentiation factor-88

Mø:

Macrophage

NEUT:

Neutrophil

NF‐κB:

Nuclear factor‐κB;

NK cell:

Natural killer cell

NLR:

Nod-like receptors

PAMP:

Pathogen-associated molecular pattern

PAR:

Protease-activated receptor

pDC:

Plasmacytoid dendritic cell

PD-L1:

Programmed death ligand-1

PGE2:

Prostaglandin E2

ROS:

Reactive oxygen species

PRR:

Pattern recognition receptor

SLFN4:

The myeloid differentiation factor Schlafen4

STAT:

Signal transducer and transcription factor

TAK:

TNF-α receptor-associated factor-related kinase

TAM:

Tumour-associated macrophage

TCGA:

The Cancer Genome Atlas

Th:

T helper cell

TIL:

Tumour infiltrating lymphocyte

Tim-3:

 T cell immunoglobulin and mucin-domain-containing molecule-3

TIR:

Toll/IL-1 receptor

TLR:

Toll-like receptor

TME:

The tumour microenvironment

TNF‐α:

Tumour necrosis factor‐α

TRAF:

TNF-α receptor-associated factor

Tr-1:

Tregulatory-1

T4ss:

Type IV secretion system

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This work was supported by the Youth Program of National Natural Science Foundation of China (No. 81500169), the Hunan Province Key Laboratory of Tumour Cellular & Molecular Pathology (2016TP1015) and the Key Project of Hunan Provincial Health Commission (20201921).

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Authors and Affiliations

  1. Medical School, Cancer Research Institute, University of South China, Chang Sheng Xi Avenue 28, Hengyang City, Hunan, 421001, China

    Meiqi Liu, Zhizhong Hu, Chengkun Wang & Yang Zhang

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  1. Meiqi Liu
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  2. Zhizhong Hu
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  3. Chengkun Wang
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  4. Yang Zhang
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Meiqi Liu is responsible for writing the article. Zhizhong Hu is responsible for figure modification and article format adjustment. Yang Zhang and Chengkun Wang are responsible for the direction and core of the article. All authors have read and approved the publication of this article.

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Correspondence to Chengkun Wang or Yang Zhang.

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Liu, M., Hu, Z., Wang, C. et al. The TLR/MyD88 signalling cascade in inflammation and gastric cancer: the immune regulatory network of Helicobacter pylori. J Mol Med 101, 767–781 (2023). https://doi.org/10.1007/s00109-023-02332-5

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  • DOI: https://doi.org/10.1007/s00109-023-02332-5

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