Fusobacterium nucleatum induces fetal death in mice via stimulation of TLR4-mediated placental inflammatory response
Fusobacterium nucleatum induces fetal death in mice via stimulation of TLR4-mediated placental inflammatory response
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DOI：
10.4049/jimmunol.179.4.2501
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发表时间：
2007-08-15
影响因子：
4.4
通讯作者：
Han, Yiping W.
中科院分区：
文献类型：
--
作者：
Liu, Hongqi;Redline, Raymond W.;Han, Yiping W.
子宫内感染在早产（PTB）中起关键作用并且以炎症为特征。目前，没有有效的治疗方法可用于治疗或预防细菌诱导的PTB。以常与PTB相关的革兰氏阴性厌氧菌具核梭杆菌为模型生物，研究宫内感染的机制。此前，已有证据表明F. nucleatum诱发小鼠早产和足月死胎。梭菌引起的胎盘感染的特点是局部细菌定植，炎症和坏死。在本研究中，F. nucleatum在体外可激活TLR 2和TLR 4。在体内，TLR 4缺陷小鼠（C57 BL/6 TLR 4（-/-）和C3 H/HeJ（TLR 4 d/d））的胎儿死亡率显著降低，但TLR 2缺陷小鼠（C57 BL/6 TLR 2（-/-））的胎儿死亡率没有显著降低。细胞核感染。TLR 4缺陷小鼠的胎儿死亡减少伴随着C57 BL/6 TLR 4（-/-）和C3 H/HeJ的胎盘坏死性炎症反应减少。在C3 H/HeJ中观察到胎盘中细菌定植减少，但在C57 BL/6 TLR 4（-/-）中未观察到。这些结果表明，炎症，而不是细菌本身，是胎儿丢失的可能原因。TLR 2似乎并不重要，因为在C57 BL/6和C57 BL/6 TLR 2（-/-）小鼠之间没有观察到细菌定植、炎症或坏死的差异。合成的TLR 4拮抗剂TLR 4A，显着减少梭菌引起的胎儿死亡和蜕膜坏死，而不影响细菌定植在胎盘。TLR 4A没有杀菌活性，也不影响假感染小鼠的出生结果。TLR 4A可能有希望作为抗炎剂用于治疗或预防细菌诱导的早产。
intrauterine infection plays a pivotal role in preterm birth (PTB) and is characterized by inflammation. Currently, there is no effective therapy available to treat or prevent bacterial- induced PTB. Using Fusobacterium nucleatum, a Gram-negative anaerobe frequently associated with PTB, as a model organism, the mechanism of intrauterine infection was investigated. Previously, it was shown that F. nucleatum induced preterm and term stillbirth in mice. Fusobacterial-induced placental infection was characterized by localized bacterial colonization, inflammation, and necrosis. In this study, F. nucleatum was shown to activate both TLR2 and TLR4 in vitro. In vivo, the fetal death rate was significantly reduced in TLR4-deficient mice (C57BL/6 TLR4(-/-) and C3H/HeJ (TLR4 d/d)), but not in TLR2-deficient mice (C57BL/6 TLR2(-/-)), following F. nucleatum infection. The reduced fetal death in TLR4-deficient mice was accompanied by decreased placental necroinflammatory responses in both C57BL/6 TLR4(-/-) and C3H/HeJ. Decreased bacterial colonization in the placenta was observed in C3H/HeJ, but not in C57BL/6 TLR4(-/-). These results suggest that inflammation, rather than the bacteria per se, was the likely cause of fetal loss. TLR2 did not appear to be critically involved, as no difference in bacterial colonization, inflammation, or necrosis was observed between C57BL/6 and C57BL/6 TLR2(-/-) mice. A synthetic TLR4 antagonist, TLR4A, significantly reduced fusobacterial-induced fetal death and decidual necrosis without affecting the bacterial colonization in the placentas. TLR4A had no bactericidal activity nor did it affect the birth outcome in sham-infected mice. TLR4A could have promise as an anti-inflammatory agent for the treatment or prevention of bacterial-induced preterm birth.