TY - JOUR
T1 - Toll-like receptor regulation of intestinal development and inflammation in the pathogenesis of necrotizing enterocolitis
AU - Lu, Peng
AU - Sodhi, Chhinder P.
AU - Hackam, David J.
N1 - Funding Information:
DJH is supported by The Hartwell Foundation, Memphis, TN and R01GM078238 , RO1DK08752 and P50GM053789 from the NIH .
PY - 2014/2
Y1 - 2014/2
N2 - Toll-like receptors (TLRs) are a structurally related family of molecules that respond to a wide variety of endogenous and exogenous ligands, and which serve as important components of the innate immune system. While TLRs have established roles in host defense, these molecules have also been shown to play important roles in the development of various disease states. A particularly important example of the role of TLRs in disease induction includes necrotizing enterocolitis (NEC), which is the most common gastrointestinal disease in preterm infants, and which is associated with extremely high morbidity and mortality rates. The development of NEC is thought to reflect an abnormal interaction between microorganisms and the immature intestinal epithelium, and emerging evidence has clearly placed the spotlight on an important and exciting role for TLRs, particularly TLR4, in NEC pathogenesis. In premature infants, TLR4 signaling within the small intestinal epithelium regulates apoptosis, proliferation and migration of enterocytes, affects the differentiation of goblet cells, and reduces microcirculatory perfusion, which in combination result in the development of NEC. This review will explore the signaling properties of TLRs on hematopoietic and non-hematopoietic cells, and will examine the role of TLR4 signaling in the development of NEC. In addition, the effects of dampening TLR4 signaling using synthetic and endogenous TLR4 inhibitors and active components from amniotic fluid and human milk on NEC severity will be reviewed. In so doing, we hope to present a balanced approach to the understanding of the role of TLRs in both immunity and disease pathogenesis, and to dissect the precise roles for TLR4 in both the cause and therapeutic intervention of necrotizing enterocolitis.
AB - Toll-like receptors (TLRs) are a structurally related family of molecules that respond to a wide variety of endogenous and exogenous ligands, and which serve as important components of the innate immune system. While TLRs have established roles in host defense, these molecules have also been shown to play important roles in the development of various disease states. A particularly important example of the role of TLRs in disease induction includes necrotizing enterocolitis (NEC), which is the most common gastrointestinal disease in preterm infants, and which is associated with extremely high morbidity and mortality rates. The development of NEC is thought to reflect an abnormal interaction between microorganisms and the immature intestinal epithelium, and emerging evidence has clearly placed the spotlight on an important and exciting role for TLRs, particularly TLR4, in NEC pathogenesis. In premature infants, TLR4 signaling within the small intestinal epithelium regulates apoptosis, proliferation and migration of enterocytes, affects the differentiation of goblet cells, and reduces microcirculatory perfusion, which in combination result in the development of NEC. This review will explore the signaling properties of TLRs on hematopoietic and non-hematopoietic cells, and will examine the role of TLR4 signaling in the development of NEC. In addition, the effects of dampening TLR4 signaling using synthetic and endogenous TLR4 inhibitors and active components from amniotic fluid and human milk on NEC severity will be reviewed. In so doing, we hope to present a balanced approach to the understanding of the role of TLRs in both immunity and disease pathogenesis, and to dissect the precise roles for TLR4 in both the cause and therapeutic intervention of necrotizing enterocolitis.
KW - Amniotic fluid
KW - Endothelium
KW - Epithelium
KW - Intestinal inflammation
KW - Necrotizing enterocolitis
KW - Toll-like receptor 4
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U2 - 10.1016/j.pathophys.2013.11.007
DO - 10.1016/j.pathophys.2013.11.007
M3 - Article
C2 - 24365655
AN - SCOPUS:84896087245
SN - 0928-4680
VL - 21
SP - 81
EP - 93
JO - Pathophysiology
JF - Pathophysiology
IS - 1
ER -