GSDMD deficiency mitigates intestinal damage via macrophage pyroptosis control in experimental NEC
Yihang Yang1,2,3, Xinyi Yang1,2,3,4, Yue Ma1,3,5
1Department of pediatrics, Chongqing Health Center for Women and Children, Women and Children's Hospital of Chongqing Medical University, 120 Longshan Rd, Chongqing, 401147, People's Republic of China.
Abstract:
Necrotizing enterocolitis (NEC) is primarily associated with an intensified inflammatory response within macrophage inflammasomes. This increased activity initiates pyroptotic cell death in macrophages, a process meticulously regulated by the protein gasdermin D (GSDMD). The precise role of macrophage pyroptosis in NEC is yet to be comprehensively understood. Our research explores the critical role of GSDMD in macrophage pyroptosis during experimental NEC. We have discovered a significant correlation between GSDMD and macrophage pyroptosis in the terminal ileum of infants afflicted with NEC. By utilizing GSDMD-deficient models and disulfiram, a compound that disrupts GSDMD-mediated pore formation, we observed a significant alleviation of NEC symptoms in mouse pups, along with a reduced presence of intestinal macrophages. Furthermore, bone marrow-derived macrophages (BMDMs) from GSDMD-deficient mice showed a decrease in overall macrophage numbers and a shift away from M1 polarization. Interestingly, although GSDMD inhibition bolstered the antibacterial capabilities of macrophages, their phagocytic activity towards zymosan particles remained unchanged. In summary, our findings underscore the essential function of GSDMD in regulating macrophage inflammasome responses and suggest that GSDMD could serve as a potential therapeutic target for NEC.
Insights
Gasdermin D (GSDMD) drives macrophage pyroptosis in necrotizing enterocolitis (NEC). Inhibiting GSDMD alleviates NEC symptoms and reduces intestinal macrophages, suggesting GSDMD as a therapeutic target for NEC.
Area of Science:
- Immunology
- Gastroenterology
- Cell Biology
Background:
- Necrotizing enterocolitis (NEC) involves heightened inflammatory responses mediated by macrophage inflammasomes.
- Macrophage pyroptosis, regulated by gasdermin D (GSDMD), is implicated in NEC pathogenesis but its precise role remains unclear.
Purpose of the Study:
- To investigate the critical role of GSDMD in macrophage pyroptosis during experimental NEC.
- To explore GSDMD as a potential therapeutic target for NEC.
Main Methods:
- Utilized GSDMD-deficient mouse models and disulfiram to inhibit GSDMD-mediated pore formation.
- Analyzed macrophage pyroptosis, numbers, polarization (M1/M2), and function (antibacterial and phagocytic) in experimental NEC.
- Correlated GSDMD expression with macrophage pyroptosis in infant NEC ileum tissue.
Main Results:
- Significant correlation found between GSDMD and macrophage pyroptosis in infant NEC ileum.
- GSDMD deficiency or inhibition significantly alleviated NEC symptoms in mouse pups.
- Reduced intestinal macrophage presence and a shift away from M1 polarization observed in GSDMD-deficient models.
- GSDMD inhibition enhanced macrophage antibacterial activity without affecting zymosan phagocytosis.
Conclusions:
- GSDMD is essential for regulating macrophage inflammasome responses in NEC.
- Targeting GSDMD presents a promising therapeutic strategy for necrotizing enterocolitis.
- Further research into GSDMD's role could lead to novel NEC treatments.
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