Department of Pediatric Orthopedics, Shengjing Hospital of China Medical University, Shenyang, China.
Department of Neonatal Intensive Care Unit, Affiliated Shenzhen Maternity and Child Healthcare Hospital, Southern Medical University, Shenzhen, China.
Pediatr Res. 2022 Jan;91(1):73-82. doi: 10.1038/s41390-021-01457-y. Epub 2021 Mar 17.
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.
The 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.
Necroptotic 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.
Necroptosis 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.
Necroptosis 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.
导致屏障功能障碍的剧烈肠道上皮细胞死亡是新生儿坏死性小肠结肠炎 (NEC) 的机制之一，其中 Toll 样受体 4 (TLR4) 起着关键作用。本研究探讨了 NEC 中细胞死亡的一种剧烈方式——坏死性细胞凋亡的作用。
检测 NEC 肠组织中坏死性细胞凋亡蛋白的表达，并与对照组进行比较。在新生野生型小鼠中诱导 NEC，并给予坏死性细胞凋亡抑制剂，以观察 NEC 是否可以缓解。进行一般情况、宏观评分和组织学评估。测量紧密连接蛋白、炎症细胞因子和坏死性细胞凋亡相关蛋白的表达，并检查屏障功能。然后，在 TLR4 敲除幼鼠中诱导 NEC，以确认 TLR4 在坏死性细胞凋亡中的作用。
坏死性细胞凋亡蛋白在 NEC 患者和动物模型中均显著上调，同时伴有 TLR4 的表达。坏死性细胞凋亡抑制剂 necrostatin-1s 可缓解 NEC，并减少炎症浸润。NEC 诱导后，TLR4 敲除小鼠的组织降解程度较轻，坏死性细胞凋亡较少。
坏死性细胞凋亡是 NEC 的一个重要病理过程。TLR4 可能是 NEC 中坏死性细胞凋亡的一种刺激物。抑制肠道细胞坏死性细胞凋亡可能是治疗 NEC 的一种有效策略。
坏死性细胞凋亡是 NEC 的关键病理过程，似乎涉及 TLR4。抗坏死性细胞凋亡治疗是一种有前途的策略，可以显著缓解 NEC 的症状。
