ST2 gene deficiency alleviates acute gastric injury in mice by modulating inflammation and epithelial cell death

Abstract

BACKGROUND

Peptic ulcer disease continues to pose a major clinical challenge worldwide. A better understanding of molecular mechanisms underlying gastric mucosal damage could open new avenues for targeted interventions. The interleukin-33 (IL-33)/suppression of tumorigenicity 2 (ST2) signaling pathway is an important regulator of inflammation and epithelial injury.

AIM

To investigate the effect of ST2 deletion on multiple pathways of inflammation and epithelial cell death in an experimental model of acute gastric injury.

METHODS

Acute gastric damage was induced in ST2^-/- and wild-type BALB/c mice by oral administration of 80% ethanol, followed by macroscopic and histological evaluation. Gastric tissue and serum were analyzed by quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, immunohistochemistry, and flow cytometry to assess cytokine production, immune cell recruitment, inflammatory signaling, and cell death pathways. Recombinant IL-33 was administered intraperitoneally in selected groups to confirm functional relevance.

RESULTS

ST2 deletion ameliorates acute gastric injury in mice, as evidenced by reduced macroscopic lesions and more preserved mucosal architecture. This was associated with decreased infiltration of neutrophils, macrophages, dendritic cells, eosinophils, CD8+ T cells, and ILC2s, along with reduced production of pro-inflammatory cytokines (IL-1β, tumor necrosis factor-α, IL-17 and interferon-γ). Moreover, ST2 gene deficiency downregulated nuclear factor kappa B (NF-κB) and NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome signaling pathways in gastric tissue, leading to diminished release of IL-1β, tumor necrosis factor-α and interferon-γ in gastric-infiltrating neutrophils and macrophages. In addition, ST2 deletion limited epithelial cell apoptosis, while recombinant IL-33 administration significantly exacerbated gastric mucosal injury, confirming the pathogenic role of IL-33/ST2 signaling.

CONCLUSION

Our study provides evidence that ST2 gene deficiency alleviates acute gastric injury effectively by suppressing inflammation mainly via repression of NF-κB and NLRP3 inflammasome signaling, and concurrently downregulating epithelial cell death. Obtained data suggest that targeting IL-33/ST2 axis represent a promising therapeutic strategy for acute gastric ulcer disease.

Keywords: Interleukin-33/suppression of tumorigenicity 2 axis; Acute gastric injury; Nuclear factor kappa B; NLRP3 inflammasome; Cell death; Peptic ulcer; Interleukin 33; Suppression of tumorigenicity 2 receptor

Core Tip: Our study shows that suppression of tumorigenicity 2 deletion markedly reduces acute gastric mucosal injury by limiting nuclear factor kappa B and NOD-like receptor family, pyrin domain containing 3 inflammatory signaling, and subsequently immune cell infiltration, proinflammatory cytokine secretion, as well as epithelial cell death. These findings provide mechanistic insight into how interleukin-33/suppression of tumorigenicity 2 drives gastric mucosal damage and highlight this pathway as a potential therapeutic target in acute gastric injury.