title: A critical role for TLR4 induction of autophagy in the regulation of enterocyte migration and the pathogenesis of necrotizing enterocolitis.
abstract: Necrotizing enterocolitis (NEC) develops in response to elevated 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 (TLR4(ΔIEC)) 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 with 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 (ATG7(ΔIEC)), the induction of autophagy was determined to be required for and not merely a consequence of NEC, because ATG7(ΔIEC) 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.
authors: Division of Pediatric Surgery, Department of Surgery, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
authors: Matthew D
authors: MD
authors: Neal
authors: Chhinder P
authors: CP
authors: Sodhi
authors: Mitchell
authors: M
authors: Dyer
authors: Brian T
authors: BT
authors: Craig
authors: Misty
authors: M
authors: Good
authors: Hongpeng
authors: H
authors: Jia
authors: Ibrahim
authors: I
authors: Yazji
authors: Amin
authors: A
authors: Afrazi
authors: Ward M
authors: WM
authors: Richardson
authors: Donna
authors: D
authors: Beer-Stolz
authors: Congrong
authors: C
authors: Ma
authors: Thomas
authors: T
authors: Prindle
authors: Zachary
authors: Z
authors: Grant
authors: Maria F
authors: MF
authors: Branca
authors: John
authors: J
authors: Ozolek
authors: David J
authors: DJ
authors: Hackam
mesh_terms: D000818:Animals; D001343:Autophagy / Q000235:genetics; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics; D004195:Disease Models, Animal; D020345:Enterocolitis, Necrotizing / Q000209:etiology* / Q000473:pathology; D020895:Enterocytes / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism
chemical_list: D051197:Toll-Like Receptor 4; D020741:rho GTP-Binding Proteins