A critical role for TLR4 induction of autophagy in the regulation of enterocyte migration and the pathogenesis of necrotizing enterocolitis

Matthew D. Neal, Chhinder P. Sodhi, Mitchell Dyer, Brian T. Craig, Misty Good, Hongpeng Jia, Ibrahim Yazji, Amin Afrazi, Ward M. Richardson, Donna Beer-Stolz, Congrong Ma, Thomas Prindle, Zachary Grant, Maria F. Branca, John Ozolek, David J. Hackam

Research output: Contribution to journalArticlepeer-review

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 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.

Original languageEnglish (US)
Pages (from-to)3541-3551
Number of pages11
JournalJournal of Immunology
Volume190
Issue number7
DOIs
StatePublished - Apr 1 2013
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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