Helicobacter pylori-induced PPFIA4 orchestrates immune network-promoting gastritis and gastric bacterial colonization
Pan Wang1,2,3, Nan You4, Yong-Sheng Teng5
1Department of Gastroenterology, The 940 Hospital of Joint Logistic Support Force of PLA, Lanzhou, China.
Abstract:
Bacteria-modulated gastric epithelial cells (GECs) play key roles in Helicobacter pylori-associated pathology. Here, we demonstrate both procolonization and proinflammation roles of GEC-derived PPFIA4 in H. pylori infection. PPFIA4 was elevated in GECs from gastric mucosa of H. pylori-infected patients and mice. PPFIA4 could be synergistically induced by H. pylori and IL-33 via the CagA/AP1 pathway. Human gastric PPFIA4 correlated with H. pylori colonization and the severity of gastritis, and H. pylori colonization and inflammation were attenuated in Ppfia4ΔGEC mice. Mechanistically, PPFIA4's SAM1 domain bound domains from CaMK to the first L27 of CASK and subsequently formed a PPFIA4/CASK/AKT1 complex to activate AKT1, resulting in NF-κB activation and MMP1/CXCL3 secretion. This not only led to decreased E-cadherin and ZO-1 by MMP1, thereby promoting gastric mucosal damage to foster H. pylori colonization, but also resulted in increased gastric influx of G-MDSCs via CXCL3-dependent migration, thereby promoting gastritis and impairing H. pylori-specific IFN-γ-producing CD4+ T cell responses to foster H. pylori colonization. Furthermore, we identified a PPFIA4 inhibitor, kira6, which effectively inhibited GEC's MMP1/CXCL3 production and ameliorated gastric H. pylori colonization and gastritis. Overall, PPFIA4 could be a promising therapeutic target, as it collectively ensures H. pylori persistence and promotes gastritis.
Insights
PPFIA4 in gastric epithelial cells promotes Helicobacter pylori colonization and gastritis by damaging the stomach lining and recruiting immune cells. Inhibiting PPFIA4 with kira6 reduced H. pylori infection and inflammation.
Area of Science:
- Gastroenterology
- Cell Biology
- Immunology
Background:
- Gastric epithelial cells (GECs) are crucial in Helicobacter pylori (H. pylori) infection pathology.
- The role of GEC-derived proteins in H. pylori-associated diseases requires further elucidation.
Purpose of the Study:
- To investigate the role of PPFIA4 in GECs during H. pylori infection.
- To explore the molecular mechanisms by which PPFIA4 influences H. pylori colonization and gastritis.
- To evaluate PPFIA4 as a potential therapeutic target.
Main Methods:
- Quantification of PPFIA4 in GECs from H. pylori-infected patients and mice.
- Investigation of PPFIA4 induction pathways involving H. pylori, IL-33, CagA, and AP1.
- Analysis of H. pylori colonization and gastritis severity in Ppfia4ΔGEC mice.
- Identification of PPFIA4-interacting proteins and downstream signaling pathways (CaMK, CASK, AKT1, NF-κB).
- Assessment of MMP1 and CXCL3 secretion and their effects on gastric barrier integrity and immune cell recruitment.
- Evaluation of the PPFIA4 inhibitor kira6 in vitro and in vivo.
Main Results:
- PPFIA4 expression is elevated in H. pylori-infected GECs and induced by H. pylori and IL-33 via CagA/AP1.
- Gastric PPFIA4 levels correlate with H. pylori colonization and gastritis severity.
- Ppfia4 deficiency in GECs attenuates H. pylori colonization and inflammation.
- PPFIA4 forms a complex with CASK and AKT1, activating AKT1 and subsequently NF-κB.
- Activated NF-κB drives MMP1 and CXCL3 secretion, leading to E-cadherin/ZO-1 degradation and G-MDSC recruitment.
- Kira6 inhibits PPFIA4-mediated MMP1/CXCL3 production, reducing H. pylori colonization and gastritis.
Conclusions:
- GEC-derived PPFIA4 plays dual roles in promoting H. pylori colonization and gastritis.
- PPFIA4 facilitates H. pylori persistence by disrupting the gastric barrier and modulating immune responses.
- Targeting PPFIA4 with inhibitors like kira6 offers a potential therapeutic strategy against H. pylori infection.
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