A critical role for TLR4 induction of autophagy in the regulation of enterocyte migration and the pathogenesis of necrotizing enterocolitis. J Immunol 2013 Apr 01;190(7):3541-51
Date
03/05/2013Pubmed ID
23455503Pubmed Central ID
PMC3608826DOI
10.4049/jimmunol.1202264Scopus ID
2-s2.0-84875469082 (requires institutional sign-in at Scopus site) 129 CitationsAbstract
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.
Author List
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 DJAuthors
Brian T. Craig MD Assistant Professor in the Surgery department at Medical College of WisconsinMitchell R. Dyer MD Assistant Professor in the Surgery department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAutophagy
Cell Line
Cell Movement
Disease Models, Animal
Enterocolitis, Necrotizing
Enterocytes
Humans
Intestinal Mucosa
Mice
Mice, Transgenic
Toll-Like Receptor 4
rho GTP-Binding Proteins
