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GPAT3 is a novel inflammatory protein promoting gastric bacterial colonization and gastritis in Helicobacter pylori infection

ABSTRACT: Bacterial-modulated gastric epithelial cells (GECs) play key roles in H. pylori-associated pathology. Here we demonstrate a pro-colonization and pro-inflammation role of GEC-expressed glycerol-3-phosphate acyltransferase 3 (GPAT3), a lipid metabolism-associated protein, in H. pylori infection. GPAT3 expression was elevated in gastric mucosa of both patients and mice infected with H. pylori. GPAT3 in GECs was synergistically induced by H. pylori and IL-22 in a cagA-dependent manner. Human gastric GPAT3 correlated with H. pylori colonization and the severity of gastritis, and mouse GPAT3 from non-bone marrow-derived cells promoted bacteria colonization and inflammation. Importantly, H. pylori colonization and inflammation were attenuated in Il22-/-, Gpat3-/- and Il22-/-Gpat3-/- mice. Mechanistically, GPAT3 directly interacted with CCAR1 and activated IKKγ, subsequently promoted NF-κB phosphorylation whereby NF-kB directly bound to the promoters of MMP1, CXCL11 and IL-33 to activate their transcription, which not only led to decreased E-cadherin and zonula occludens-1 proteins by MMP1, thereby resulting in gastric mucosal damage and increased H. pylori colonization; but also resulted in increased gastric influx of CD8+ T cells via CXCL11-dependent migration and their subsequent IL-33-dependent IFN-γ production, thereby promoting H. pylori-associated gastritis. Overall, we propose a model in which GPAT3 collectively ensures H. pylori persistence and promotes gastritis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE264450 | GEO | 2024/04/26

REPOSITORIES: GEO

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Project description:The model is first model of tissue level cellular immune responses to H. pylori in the publication, "Modeling the role of lanthionine synthetase C-like 2 (LANCL2) in the modulation of immune responses to Helicobacter pylori infection" in PlosOne by Leber, Bassaganya-Riera, Tubau-Juni, Zoccoli-Rodriguez, Viladomiu, Abedi, Lu, and Hontecillas. Abstract: Immune responses to Helicobacter pylori are orchestrated through complex balances of host-bacterial interactions, including inflammatory and regulatory immune responses across scales that can lead to the development of the gastric disease or the promotion of beneficial systemic effects. While inflammation in response to the bacterium has been reasonably characterized, the regulatory pathways that contribute to preventing inflammatory events during H. pylori infection are incompletely understood. To aid in this effort, we have generated a computational model incorporating recent developments in the understanding of H. pylori-host interactions. Sensitivity analysis of this model reveals that a regulatory macrophage population is critical in maintaining high H. pylori colonization without the generation of an inflammatory response. To address how this myeloid cell subset arises, we developed a second model describing an intracellular signaling network for the differentiation of macrophages. Modeling studies predicted that LANCL2 is a central regulator of inflammatory and effector pathways and its activation promotes regulatory responses characterized by IL-10 production while suppressing effector responses. The predicted impairment of regulatory macrophage differentiation by the loss of LANCL2 was simulated based on multiscale linkages between the tissue-level gastric mucosa and the intracellular models. The simulated deletion of LANCL2 resulted in a greater clearance of H. pylori, but also greater IFNγ responses and damage to the epithelium. The model predictions were validated within a mouse model of H. pylori colonization in wild-type (WT), LANCL2 whole body KO and myeloid-specific LANCL2-/- (LANCL2Myeloid) mice, which displayed similar decreases in H. pylori burden, CX3CR1+ IL-10-producing macrophages, and type 1 regulatory (Tr1) T cells. This study shows the importance of LANCL2 in the induction of regulatory responses in macrophages and T cells during H. pylori infection.

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GPAT3 is a novel inflammatory protein promoting gastric bacterial colonization and gastritis in Helicobacter pylori infection

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