Nod1 Imprints Inflammatory and Carcinogenic Responses toward the Gastric Pathogen Helicobacter pylori

• Published in: Cancer research (Chicago, Ill.) Vol. 79; no. 7; pp. 1600 - 1611
• Main Authors: Suarez, Giovanni, Romero-Gallo, Judith, Piazuelo, Maria B, Sierra, Johanna C, Delgado, Alberto G, Washington, M Kay, Shah, Shailja C, Wilson, Keith T, Peek, Jr, Richard M
• Format: Journal Article
• Language: English
• Published: United States 01.04.2019
• Subjects: Animals; Carcinogenesis; Cytokines - biosynthesis; Gastric Mucosa - metabolism; Helicobacter pylori - pathogenicity; Mice; Mice, Inbred C57BL; Mice, Knockout; Nod1 Signaling Adaptor Protein - genetics; Nod1 Signaling Adaptor Protein - physiology; Stomach Neoplasms - immunology; Stomach Neoplasms - microbiology
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-18-2651

( ) is the strongest known risk for gastric cancer. The type IV secretion system is an oncogenic locus that translocates peptidoglycan into host cells, where it is recognized by NOD1, an innate immune receptor. Beyond this, the role of NOD1 in -induced cancer remains undefined. To address this knowledge gap, we infected two genetic models of Nod1 deficiency with the strain PMSS1: C57BL/6 mice, which rarely develop cancer, and INS-GAS FVB/N mice, which commonly develop cancer. Infected C57BL/6 and INS-GAS mice acutely developed more severe gastritis, and INS-GAS mice developed gastric dysplasia more frequently compared with mice. Because genotype status did not alter microbial phenotypes of adapted , we investigated host immunologic responses. infection of mice led to significantly increased gastric mucosal levels of Th1, Th17, and Th2 cytokines compared with Nod1 wild-type (WT) mice. To define the role of specific innate immune cells, we quantified cytokine secretion from -infected primary gastric organoids generated from WT or mice that were cocultured with or without WT or macrophages. Infection increased cytokine production from gastric epithelial cells and macrophages and elevations were significantly increased with Nod1 deficiency. Furthermore, infection altered the polarization status of macrophages compared with macrophages. Collectively, these studies demonstrate that loss of Nod1 augments inflammatory and injury responses to . Nod1 may exert its restrictive role by altering macrophage polarization, leading to immune evasion and microbial persistence. SIGNIFICANCE: These findings suggest that manipulation of NOD1 may represent a novel strategy to prevent or treat pathologic outcomes induced by infection.