A critical role for TLR4 induction of autophagy in the regulation of enterocyte migration and the pathogenesis of necrotizing enterocolitis.
A critical role for TLR4 induction of autophagy in the regulation of enterocyte migration and the pathogenesis of necrotizing enterocolitis.
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DOI：
10.4049/jimmunol.1202264
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发表时间：
2013-04-01
期刊：
影响因子：
--
通讯作者：
Hackam DJ
中科院分区：
文献类型：
--
作者：
Neal MD;Sodhi CP;Dyer M;Craig BT;Good M;Jia H;Yazji I;Afrazi A;Richardson WM;Beer-Stolz D;Ma C;Prindle T;Grant Z;Branca MF;Ozolek J;Hackam DJ
坏死性小肠结肠炎(NEC)是新生儿肠上皮细胞Toll样受体-4(TLR4)信号升高的反应，其特征是TLR4介导的肠细胞迁移抑制和粘膜愈合降低。TLR4损伤粘膜愈合的下游过程仍不完全清楚。在其他系统中，TLR4诱导自噬，这是一种对细胞压力的适应性反应。我们现在假设TLR4诱导肠细胞自噬，TLR4诱导的自噬在NEC的发展中起关键作用。利用在肠细胞中选择性缺失TLR4的小鼠(TLR4IEC)，以及在TLR4缺乏的培养的肠细胞中，我们现在证明了TLR4的激活诱导了肠细胞的自噬。与正常对照组相比，未成熟的小鼠和人类肠道中自噬基因的表达增加，而小鼠和人类的NEC的发展与肠细胞自噬的增加有关。重要的是，在我们选择性地从肠上皮(ATG7ΔIEC)中删除自噬基因的小鼠中，自噬的诱导被确定为NEC所必需的，而不仅仅是NEC的结果，因为ATG7ΔIEC小鼠受到保护，免受NEC的发育。在确定相关机制时，TLR4诱导的自噬在体外和体内都导致肠细胞迁移受损，而在培养的肠细胞中，这需要RhoA介导的应激纤维的诱导。这些发现背离了目前该领域的教条，确定了TLR4诱导的肠上皮内自噬在NEC发病机制中的独特作用，并确定了自噬对肠细胞迁移的负面影响在其发展中发挥了重要作用。
Necrotizing enterocolitis (NEC) develops in response to elevated Toll-like receptor-4 (TLR4) signaling in the newborn intestinal epithelium, and is characterized by TLR4-mediated inhibition of enterocyte migration and reduced mucosal healing. The downstream processes by which TLR4 impairs mucosal healing remain incompletely understood. In other systems, TLR4 induces autophagy, an adaptive response to cellular stress. We now hypothesize that TLR4 induces autophagy in enterocytes, and that TLR4-induced autophagy plays a critical role in NEC development. Using mice selectively lacking TLR4 in enterocytes(TLR4ΔIEC), and in TLR4-deficient cultured enterocytes, we now show that TLR4 activation induces autophagy in enterocytes. Immature mouse and human intestine showed increased expression of autophagy genes compared to full-term controls, and NEC development in both mouse and human was associated with increased enterocyte autophagy. Importantly, using mice in which we selectively deleted the autophagy gene ATG7 from the intestinal epithelium (ATG7ΔIEC), the induction of autophagy was determined to be required for and not merely a consequence of NEC, as ATG7ΔIEC mice were protected from NEC development. In defining the mechanisms involved, TLR4-induced autophagy led to impaired enterocyte migration both in vitro and in vivo, which in cultured enterocytes required the induction of RhoA-mediated stress fibers. These findings depart from current dogma in the field by identifying a unique effect of TLR4-induced autophagy within the intestinal epithelium in the pathogenesis of NEC, and identify that the negative consequences of autophagy on enterocyte migration play an essential role in its development.
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DOI：
10.4049/jimmunol.1103114
发表时间：
2012-05-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Afrazi A;Sodhi CP;Good M;Jia H;Siggers R;Yazji I;Ma C;Neal MD;Prindle T;Grant ZS;Branca MF;Ozolek J;Chang EB;Hackam DJ
通讯作者：
Hackam DJ
影响因子：
3.6
作者：
Afrazi A;Sodhi CP;Richardson W;Neal M;Good M;Siggers R;Hackam DJ
通讯作者：
Hackam DJ
影响因子：
30.8
作者：
Hampe, Jochen;Franke, Andre;Schreiber, Stefan
通讯作者：
Schreiber, Stefan
影响因子：
3.1
作者：
Cario, E;Podolsky, DK
通讯作者：
Podolsky, DK
影响因子：
5.5
作者：
Du, Jianhai;Teng, Ru-Jeng;Shi, Yang
通讯作者：
Shi, Yang