Olfactomedin 4 down-regulates innate immunity against Helicobacter pylori infection
Wenli Liu1, Ming Yan, Yueqin Liu
1Molecular and Clinical Hematology Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Abstract:
Olfactomedin 4 (OLFM4) is a glycoprotein that has been found to be up-regulated in inflammatory bowel diseases and Helicobacter pylori infected patients. However, its role in biological processes such as inflammation or other immune response is not known. In this study, we generated OLFM4 KO mice to investigate potential role(s) of OLFM4 in gastric mucosal responses to H. pylori infection. H. pylori colonization in the gastric mucosa of OLFM4 KO mice was significantly lower compared with WT littermates. The reduced bacterial load was associated with enhanced infiltration of inflammatory cells in gastric mucosa. Production and expression of proinflammatory cytokines/chemokines such as IL-1beta, IL-5, IL-12 p70, and MIP-1alpha was increased in OLFM4 KO mice compared with infected controls. Furthermore, we found that OLFM4 is a target gene of NF--kappaB pathway and has a negative feedback effect on NF-kappaB activation induced by H. pylori infection through a direct association with nucleotide oligomerization domain-1 (NOD1) and -2 (NOD2). Together these observations indicate that OLFM4 exerts considerable influence on the host defense against H. pylori infection acting through NOD1 and NOD2 mediated NF-kappaB activation and subsequent cytokines and chemokines production, which in turn inhibit host immune response and contribute to persistence of H. pylori colonization.
Insights
Olfactomedin 4 (OLFM4) deficiency enhances gastric immune responses to Helicobacter pylori infection, reducing bacterial load. OLFM4 negatively regulates immune activation, promoting H. pylori persistence.
Area of Science:
- Immunology
- Gastroenterology
- Microbiology
Background:
- Olfactomedin 4 (OLFM4) is upregulated in inflammatory conditions like inflammatory bowel disease and H. pylori infection.
- The precise function of OLFM4 in immune responses, particularly concerning H. pylori infection, remains unclear.
Purpose of the Study:
- To investigate the role of OLFM4 in the gastric mucosal immune response to H. pylori infection using knockout (KO) mice.
- To elucidate the molecular mechanisms underlying OLFM4's influence on host defense against H. pylori.
Main Methods:
- Generation and use of OLFM4 knockout (KO) mice and wild-type (WT) littermates for H. pylori infection studies.
- Assessment of bacterial colonization, inflammatory cell infiltration, and cytokine/chemokine production in gastric mucosa.
- Investigation of OLFM4's interaction with the NF-κB pathway, including NOD1 and NOD2 signaling.
Main Results:
- H. pylori colonization was significantly lower in OLFM4 KO mice compared to WT controls.
- KO mice exhibited enhanced gastric inflammatory cell infiltration and increased production of proinflammatory cytokines (IL-1β, IL-5, IL-12p70) and chemokines (MIP-1α).
- OLFM4 was identified as a target gene of the NF-κB pathway, negatively regulating NF-κB activation via direct association with NOD1 and NOD2.
Conclusions:
- OLFM4 plays a critical role in modulating host defense against H. pylori infection.
- OLFM4 negatively impacts NOD1/NOD2-mediated NF-κB activation, cytokine production, and subsequent immune responses, thereby facilitating H. pylori colonization.
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