Reciprocal expression and signaling of TLR4 and TLR9 in the pathogenesis and treatment of necrotizing enterocolitis.
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.
Gribar
Steven C
SC
Department of Surgery, Division of Pediatric Surgery, Children's Hospital of Pittsburgh, and University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Sodhi
Chhinder P
CP
Richardson
Ward M
WM
Anand
Rahul J
RJ
Gittes
George K
GK
Branca
Maria F
MF
Jakub
Adam
A
Shi
Xia-hua
XH
Shah
Sohail
S
Ozolek
John A
JA
Hackam
David J
DJ
D000818:Animals; D002460:Cell Line; D015536:Down-Regulation / Q000276:immunology; D020345:Enterocolitis, Necrotizing / Q000196:embryology / Q000276:immunology* / Q000378:metabolism / Q000628:therapy*; D020895:Enterocytes / Q000276:immunology / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000276:immunology*; D015316:Genetic Therapy; D006801:Humans; D007231:Infant, Newborn; D007413:Intestinal Mucosa / Q000196:embryology / Q000254:growth & development / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D051381:Rats; D015398:Signal Transduction / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology* / Q000627:therapeutic use; D051217:Toll-Like Receptor 9 / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation / Q000276:immunology
C495345:TLR4 protein, human; C495371:TLR9 protein, human; C493487:Tlr4 protein, mouse; C495370:Tlr9 protein, mouse; D051197:Toll-Like Receptor 4; D051217:Toll-Like Receptor 9