Nucleotide-binding oligomerization domain 1 and Helicobacter pylori infection: A review

Abstract

Nucleotide-binding oligomerization domain 1 (NOD1) is an intracellular innate immune sensor for small molecules derived from bacterial cell components. NOD1 activation by its ligands leads to robust production of pro-inflammatory cytokines and chemokines by innate immune cells, thereby mediating mucosal host defense systems against microbes. Chronic gastric infection due to Helicobacter pylori (H. pylori) causes various upper gastrointestinal diseases, including atrophic gastritis, peptic ulcers, and gastric cancer. It is now generally accepted that detection of H. pylori by NOD1 expressed in gastric epithelial cells plays an indispensable role in mucosal host defense systems against this organism. Recent studies have revealed the molecular mechanism by which NOD1 activation caused by H. pylori infection is involved in the development of chronic gastritis and gastric cancer. In this review, we have discussed and summarized how sensing of H. pylori by NOD1 mediates the prevention of chronic gastritis and gastric cancer.

Keywords: Gastric cancer; Helicobacter pylori, Gastritis; Nucleotide-binding oligomerization domain 1.

Figure 1

Nucleotide-binding oligomerization domain 1-mediated mucosal host defense against Helicobacter pylori infection. Nucleotide-binding oligomerization domain 1 (NOD1) recognizes Helicobacter pylori (H. pylori)-derived peptidoglycan (PGN) or outer membrane vesicles (OMVs). Sensing of H. pylori-derived PGN or OMVs by intracellular NOD1 in the gastric epithelial cells induces production of type I IFN and C-X-C motif chemokine ligand 10 (CXCL10) through the receptor interacting protein 2 (RIP2)-TNF receptor-associated factor 3 (TRAF3)-interferon regulatory factor 7(IRF7)-IFN-stimulated gene factor 3 (ISGF3) pathway, thereby promoting T helper type 1 (Th1) responses. ISGF3 is a heterotrimeric complex composed of signal transduction and activator of transcription 1 (Stat1), Stat2, and IRF9. NOD1 activation also induces production of anti-microbial peptides (AMPs) through nuclear translocation of nuclear factor-kappa B (NF-κB) subunits. IFN-γ and AMPs exert bactericidal effects.

Figure 2

Prevention of gastric cancer development by nucleotide-binding oligomerization domain 1. Sensing of Helicobacter pylori (H. pylori)-derived peptidoglycan (PGN) by intracellular nucleotide-binding oligomerization domain 1 (NOD1) in gastric epithelial cells induces activation of TNF receptor associated factor 3 (TRAF3) as mentioned in Figure 1. TRAF3 activation by NOD1 negatively regulates expression of caudal-related homeobox 2 (Cdx2) via the inhibition of nuclear factor-kappa B (NF-κB) activation to prevent intestinal metaplasia and gastric cancer (left panel). On the other hand, lack of NOD1-mediated negative regulation on Cdx2 expression promotes the development of gastric cancer (right panel).