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Reciprocal Expression and Signaling of TLR4 and TLR9 in the Pathogenesis and Treatment of Necrotizing Enterocolitis¹

Department of Surgery, Division of Pediatric Surgery, Children’s Hospital of Pittsburgh and Department of Pathology, Division of Pediatric Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213

Necrotizing enterocolitis (NEC) is a common and often fatal inflammatory disorder affecting preterm infants that develops upon interaction of indigenous bacteria with the premature intestine. We now demonstrate that the developing mouse intestine shows reciprocal patterns of expression of TLR4 and TLR9, the receptor for bacterial DNA (CpG-DNA). Using a novel ultrasound-guided in utero injection system, we administered LPS directly into the stomachs of early and late gestation fetuses to induce TLR4 signaling and demonstrated that TLR4-mediated signaling within the developing intestine follows its expression pattern. Murine and human NEC were associated with increased intestinal TLR4 and decreased TLR9 expression, suggesting that reciprocal TLR4 and TLR9 signaling may occur in the pathogenesis of NEC. Enteral administration of adenovirus expressing mutant TLR4 to neonatal mice reduced the severity of NEC and increased TLR9 expression within the intestine. Activation of TLR9 with CpG-DNA inhibited LPS-mediated TLR4 signaling in enterocytes in a mechanism dependent upon the inhibitory molecule IRAK-M. Strikingly, TLR9 activation with CpG-DNA significantly reduced NEC severity, whereas TLR9-deficient mice exhibited increased NEC severity. Thus, the reciprocal nature of TLR4 and TLR9 signaling within the neonatal intestine plays a role in the development of NEC and provides novel therapeutic approaches to this disease.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by National Institutes of Health Grant 1R01-GM078238-01 (to D.J.H.). S.C.G. and W.M.R. are supported in part by the Loan Repayment Program for Pediatric Research of the National Institutes of Health. S.C.G. is supported by the American College of Surgeons Research Fellowship. W.M.R. is supported by the Surgical Infection Society Resident Research Award.

² Address correspondence and reprint requests to Dr. David J. Hackam, Division of Pediatric Surgery, Room 4A-486 DeSoto Wing, Children’s Hospital of Pittsburgh, Pittsburgh, PA 15213. E-mail address: david.hackam{at}chp.edu

³ Abbreviations used in this paper: NEC, necrotizing enterocolitis; E, embryonic day; IRAK, IL-1R-associated kinase; ODN, oligodeoxynucleotide; siRNA, small interfering RNA; TRAF, TNFR-associated factor.