Abstract
BackgroundDramatic intestinal epithelial cell death leading to barrier dysfunction is one of the mechanism of neonatal necrotizing enterocolitis (NEC), in which Toll-like receptor 4 (TLR4) plays a pivotal role. This study explored the role of necroptosis, a drastic way of cell death in NEC.MethodsThe expression of necroptotic proteins was tested in NEC intestinal tissue and compared with controls. NEC was induced in neonatal wild-type mice and a necroptosis inhibitor was given to investigate whether NEC could be relieved. The general condition, macroscopic scoring, and histological evaluations were performed. The expression of tight junction proteins, inflammatory cytokines, and necroptosis-related proteins was measured, and barrier function was examined. Then, NEC was induced in TLR4-knockout pups to confirm the role of TLR4 in necroptosis.ResultsNecroptotic proteins were significantly upregulated in both NEC patient and animal models, together with the expression of TLR4. NEC could be relieved and inflammatory infiltration was decreased by necrostatin-1s. TLR4-knockout mice showed milder tissue degradation and less necroptosis after NEC induction.ConclusionsNecroptosis is an essential pathological process of NEC. TLR4 may be one stimulator of necroptosis in NEC. Inhibiting the intestinal cell necroptosis might be a useful strategy in the treatment of NEC.ImpactNecroptosis is a key pathological process in NEC, which appears to involve TLR4.Anti-necroptosis treatment is a promising strategy that could significantly relieve the symptoms of NEC.
Highlights
Neonatal necrotizing enterocolitis (NEC) is a concern due to the increased survival of preterm births
This study investigated the role of necroptosis in NEC patients and model animals
NEC patients and animals had increased intestinal necroptosis and elevated Toll-like receptor 4 (TLR4) expression Increased intestinal necroptosis was observed in human NEC bowel tissue, as demonstrated by increased pRIPK3 expression (p < 0.001) (Fig. 1a, b)
Summary
Neonatal necrotizing enterocolitis (NEC) is a concern due to the increased survival of preterm births. Dramatic intestinal epithelial cell death leading to barrier dysfunction is one of the mechanism of neonatal necrotizing enterocolitis (NEC), in which Toll-like receptor 4 (TLR4) plays a pivotal role. This study explored the role of necroptosis, a drastic way of cell death in NEC. METHODS: The expression of necroptotic proteins was tested in NEC intestinal tissue and compared with controls. NEC was induced in TLR4-knockout pups to confirm the role of TLR4 in necroptosis. RESULTS: Necroptotic proteins were significantly upregulated in both NEC patient and animal models, together with the expression of TLR4. TLR4-knockout mice showed milder tissue degradation and less necroptosis after NEC induction. Inhibiting the intestinal cell necroptosis might be a useful strategy in the treatment of NEC
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