Intestinal Epithelial Toll-Like Receptor 4 Regulates Goblet Cell Development and Is Required for Necrotizing Enterocolitis in Mice

被引：311

作者：

Sodhi, Chhinder P. ^{[1
,4
]}

Neal, Matthew D. ^{[1
,4
]}

Siggers, Richard ^{[1
,4
]}

Sho, Shonan ^{[1
,4
]}

Ma, Congrong ^{[1
,4
]}

Branca, Maria F. ^{[1
,4
]}

Prindle, Thomas, Jr. ^{[1
,4
]}

Russo, Anthony M. ^{[1
,4
]}

Afrazi, Amin ^{[1
,4
]}

Good, Misty ^{[3
,5
]}

Brower-Sinning, Rachel ^{[1
,4
]}

Firek, Brian ^{[1
,4
]}

Morowitz, Michael J. ^{[1
,4
]}

Ozolek, John A. ^{[2
,6
]}

Gittes, George K. ^{[1
,4
]}

Billiar, Timothy R. ^{[4
]}

Hackam, David J. ^{[1
,4
]}

机构：

[1] UPMC, Childrens Hosp Pittsburgh, Div Pediat Surg, Pittsburgh, PA 15224 USA

[2] Childrens Hosp Pittsburgh, Div Pathol, Pittsburgh, PA 15213 USA

[3] Childrens Hosp Pittsburgh, Div Newborn Med, Pittsburgh, PA 15213 USA

[4] Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA USA

[5] Univ Pittsburgh, Sch Med, Dept Pediat, Pittsburgh, PA 15261 USA

[6] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA USA

来源：

GASTROENTEROLOGY | 2012年 / 143卷 / 03期

基金：

美国国家卫生研究院;

关键词：

Development; Mouse Model; Microbiota; Pediatric Gastrointestinal Disorder; STEM-CELLS; BILE-ACID; SELF-RENEWAL; TLR4; EXPRESSION; PATHOGENESIS; RECOGNITION; BACTERIA; IMMATURE; BETA;

D O I：

10.1053/j.gastro.2012.05.053

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

100201 [内科学];

摘要：

BACKGROUND & AIMS: Little is known about factors that regulate intestinal epithelial differentiation; microbial recognition receptors such as Toll-like receptor (TLR)4 might be involved. We investigated whether intestinal TLR4 regulates epithelial differentiation and is involved in development of necrotizing enterocolitis (NEC) of the immature intestine. METHODS: Mice with conditional disruption of TLR4 in the intestinal epithelium and TLR4 knockout (TLR4(-/-)) mice were generated by breeding TLR4(loxp/loxp) mice with villin-cre and Ella-cre, respectively. Enterocytes that did not express or overexpressed TLR4 were created by lentiviral or adenoviral transduction. Intestinal organoids were cultured on tissue matrices. Bile acids were measured by colorimetric assays, and microbial composition was determined by 16S pyrosequencing. NEC was induced in 7- to 10-day-old mice by induction of hypoxia twice daily for 4 days. RESULTS: TLR4(-/-) mice and mice with enterocyte-specific deletion of TLR4 were protected from NEC; epithelial differentiation into goblet cells was increased via suppressed Notch signaling in the small intestinal epithelium. TLR4 also regulates differentiation of goblet cells in intestinal organoid and enterocyte cell cultures; differentiation was increased on deletion of TLR4 and restored when TLR4 was expressed ectopically. TLR4 signaling via Notch was increased in intestinal tissue samples from patients with NEC, and numbers of goblet cells were reduced. 16S pyrosequencing revealed that wild-type and TLR4-deficient mice had similar microbial profiles; increased numbers of goblet cells were observed in mice given antibiotics. TLR4 deficiency reduced levels of luminal bile acids in vivo, and addition of bile acids to TLR4-deficient cell cultures prevented differentiation of goblet cells. CONCLUSIONS: TLR4 signaling and Notch are increased in intestinal tissues of patients with NEC and required for induction of NEC in mice. TLR4 prevents goblet cell differentiation, independently of the microbiota. Bile acids might initiate goblet cell development.

引用

页码：708 / U234

页数：16

共 35 条

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Intracellular Heat Shock Protein-70 Negatively Regulates TLR4 Signaling in the Newborn Intestinal Epithelium [J].