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

被引:197
作者
Gribar, Steven C.
Sodhi, Chhinder P.
Richardson, Ward M.
Anand, Rahul J.
Gittes, George K.
Branca, Maria F.
Jakub, Adam
Shi, Xia-hua
Shah, Sohail
Ozolek, John A.
Hackam, David J. [1 ]
机构
[1] Childrens Hosp, Div Pediat Surg, Dept Surg, Pittsburgh, PA 15213 USA
基金
美国国家卫生研究院;
关键词
TOLL-LIKE RECEPTOR-4; ENTEROCYTE MIGRATION; ENDOTOXIN TOLERANCE; HEPARAN-SULFATE; BACTERIAL-DNA; IRAK-M; LIPOPOLYSACCHARIDE; PROBIOTICS; PHAGOCYTOSIS; RECOGNITION;
D O I
10.4049/jimmunol.182.1.636
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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 LIPS 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. Tire Journal of Immunology, 2009, 182: 636-646.
引用
收藏
页码:636 / 646
页数:11
相关论文
共 56 条
[1]   Hypoxia causes an increase in phagocytosis by macrophages in a HIF-1α-dependent manner [J].
Anand, Rahul J. ;
Gribar, Steven C. ;
Li, Jun ;
Kohler, Jeff W. ;
Branca, Maria F. ;
Dubowski, Theresa ;
Sodhi, Chhinder P. ;
Hackam, David J. .
JOURNAL OF LEUKOCYTE BIOLOGY, 2007, 82 (05) :1257-1265
[2]   Sepsis and evolution of the innate immune response [J].
Beutler, B ;
Poltorak, A .
CRITICAL CARE MEDICINE, 2001, 29 (07) :S2-S6
[3]   Oral probiotics prevent necrotizing enterocolitis in very low birth weight neonates [J].
Bin-Nun, A ;
Bromiker, R ;
Wilschanski, M ;
Kaplan, M ;
Rudensky, B ;
Caplan, M ;
Hammerman, C .
JOURNAL OF PEDIATRICS, 2005, 147 (02) :192-196
[4]   Postoperative outcomes of extremely low birth-weight infants with necrotizing enterocolitis or isolated intestinal perforation - A prospective cohort study by the NICHD neonatal research network [J].
Blakely, ML ;
Lally, KP ;
McDonald, S ;
Brown, RL ;
Barnhart, DC ;
Ricketts, RR ;
Thompson, WR ;
Scherer, LR ;
Klein, MD ;
Letton, RW ;
Chwals, WJ ;
Touloukian, RJ ;
Kurkchubasche, AG ;
Skinner, MA ;
Moss, RL ;
Hilfiker, ML .
ANNALS OF SURGERY, 2005, 241 (06) :984-989
[5]   Chlamydial heat shock protein 60 activates macrophages and endothelial cells through toll-like receptor 4 and MD2 in a MyD88-dependent pathway [J].
Bulut, Y ;
Faure, E ;
Thomas, L ;
Karahashi, H ;
Michelsen, KS ;
Equils, O ;
Morrison, SG ;
Morrison, RP ;
Arditi, M .
JOURNAL OF IMMUNOLOGY, 2002, 168 (03) :1435-1440
[6]   Endotoxin differentially modulates the basolateral and apical sodium/proton exchangers (NHE) in enterocytes [J].
Cetin, S ;
Dunklebarger, J ;
Li, J ;
Boyle, P ;
Ergun, O ;
Qureshi, F ;
Ford, H ;
Upperman, J ;
Watkins, S ;
Hackam, DJ .
SURGERY, 2004, 136 (02) :375-383
[7]   Endotoxin inhibits intestinal epithelial restitution through activation of Rho-GTPase and increased focal adhesions [J].
Cetin, S ;
Ford, HR ;
Sysko, LR ;
Agarwal, C ;
Wang, J ;
Neal, MD ;
Baty, C ;
Apodaca, G ;
Hackam, DJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (23) :24592-24600
[8]   Nitric oxide inhibits enterocyte migration through activation of RhoA-ATPase in a SHP-2-dependent manner [J].
Cetin, Selma ;
Leaphart, Cynthia L. ;
Li, Jun ;
Ischenko, Irene ;
Hayman, Michael ;
Upperman, Jeffrey ;
Zamora, Ruben ;
Watkins, Simon ;
Ford, Henri R. ;
Wang, James ;
Hackam, David J. .
AMERICAN JOURNAL OF PHYSIOLOGY-GASTROINTESTINAL AND LIVER PHYSIOLOGY, 2007, 292 (05) :G1347-G1358
[9]   Sepsis-induced suppression of lung innate immunity is mediated by IRAK-M [J].
Deng, Jane C. ;
Cheng, Genhong ;
Newstead, Michael W. ;
Zeng, Xianying ;
Kobayashi, Koichi ;
Flavell, Richard A. ;
Standiford, Theodore J. .
JOURNAL OF CLINICAL INVESTIGATION, 2006, 116 (09) :2532-2542
[10]   Tollip regulates proinflammatory responses to interleukin-1 and lipopolysaccharide [J].
Didierlaurent, A ;
Brissoni, B ;
Velin, D ;
Aebi, N ;
Tardivel, A ;
Käslin, E ;
Sirard, JC ;
Angelov, G ;
Tschopp, J ;
Burns, K .
MOLECULAR AND CELLULAR BIOLOGY, 2006, 26 (03) :735-742