A critical role for TLR4 in the pathogenesis of necrotizing enterocolitis by modulating intestinal injury and repair
A critical role for TLR4 in the pathogenesis of necrotizing enterocolitis by modulating intestinal injury and repair
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DOI：
10.4049/jimmunol.179.7.4808
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发表时间：
2007-10-01
影响因子：
4.4
通讯作者：
Hackam, David J.
中科院分区：
文献类型：
--
作者：
Leaphart, Cynthia L.;Cavallo, Jaime;Hackam, David J.
坏死性小肠结肠炎 (NEC) 是早产儿胃肠道疾病导致死亡的主要原因，其特征是 LPS 在发炎肠道中易位。我们假设 LPS 受体 (TLR4) 在 NEC 发育中发挥着关键作用，并且我们试图确定所涉及的机制。我们现在证明，小鼠和人类的 NEC 与肠粘膜中 TLR4 表达增加有关，并且与 NEC 发育相关的生理应激源（即暴露于 LPS 和缺氧）通过上调 TLR4 使小鼠肠上皮对 LPS 敏感。为了支持 TLR4 在 NEC 发育中的关键作用，与野生型 C3H/HeOUJ 同窝小鼠相比，TLR4 突变 C3H/HeJ 小鼠免受 NEC 发育。 TLR4 体外激活导致肠上皮细胞凋亡增加，肠上皮细胞迁移和增殖减少，表明 TLR4 在肠道修复中发挥作用。与突变小鼠相比，C3H/HeOUJ 小鼠中 NEC 严重程度的增加是由于粘膜损伤后肠上皮细胞凋亡增加以及肠上皮细胞恢复和增殖减少所致，这支持了这种可能性。 TLR4 信号传导还导致肠粘着斑激酶 (FAK) 丝氨酸磷酸化增加。值得注意的是，TLR4 与 FAK 发生免疫共沉淀，并且小干扰 RNA 介导的 FAK 抑制在 TLR4 激活后恢复了肠上皮细胞迁移，表明 FAK-TLR4 关联调节肠道愈合。这些发现证明TLR4通过影响肠上皮细胞损伤和修复在NEC发展中发挥关键作用，确定了调节肠上皮细胞迁移的新型TLR4-FAK关联，并建议TLR4/FAK作为该疾病的治疗靶点。
Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in preterm infants and is characterized by translocation of LPS across the inflamed intestine. We hypothesized that the LPS receptor,(TLR4) plays a critical role in NEC development, and we sought to determine the mechanisms involved. We now demonstrate that NEC in mice and humans is associated with increased expression of TLR4 in the intestinal mucosa and that physiological stressors associated with NEC development, namely, exposure to LPS and hypoxia, sensitize the murine intestinal epithelium to LPS through up-regulation of TLR4. In support of a critical role for TLR4 in NEC development, TLR4-mutant C3H/HeJ mice were protected from the development of NEC compared with wild-type C3H/HeOUJ littermates. TLR4 activation in vitro led to increased enterocyte apoptosis and reduced enterocyte migration and proliferation, suggesting a role for TLR4 in intestinal repair. In support of this possibility, increased NEC severity in C3H/HeOUJ mice resulted from increased enterocyte apoptosis and reduced enterocyte restitution and proliferation after mucosal injury compared with mutant mice. TLR4 signaling also led to increased serine phosphorylation of intestinal focal adhesion kinase (FAK). Remarkably, TLR4 coimmunoprecipitated with FAK, and small interfering RNA-mediated FAK inhibition restored enterocyte migration after TLR4 activation, demonstrating that the FAK-TLR4 association regulates intestinal healing. These findings demonstrate a critical role for TLR4 in the development of NEC through effects on enterocyte injury and repair, identify a novel TLR4-FAK association in regulating enterocyte migration, and suggest TLR4/FAK as a therapeutic target in this disease.