Toll-like Receptor 4-mediated Endoplasmic Reticulum Stress in Intestinal Crypts Induces Necrotizing Enterocolitis*

被引：144

作者：

Afrazi, Amin ^{[1
,4
]}

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

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

Good, Misty ^{[3
,5
]}

Yamaguchi, Yukihiro ^{[1
,4
]}

Egan, Charlotte E. ^{[1
,4
]}

Lu, Peng ^{[1
,4
]}

Jia, Hongpeng ^{[1
,4
]}

Shaffiey, Shahab ^{[1
,4
]}

Lin, Joyce ^{[1
,4
]}

Ma, Congrong ^{[1
,4
]}

Vincent, Garrett ^{[1
,4
]}

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

Weyandt, Samantha ^{[1
,4
]}

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

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

Wiersch, John ^{[1
,4
]}

Tschurtschenthaler, Markus ^{[7
]}

Shiota, Chiyo ^{[1
,4
]}

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

Billiar, Timothy R. ^{[4
]}

Mollen, Kevin ^{[1
,4
]}

Kaser, Arthur ^{[7
]}

Blumberg, Richard ^{[8
]}

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

机构：

[1] Univ Pittsburgh, Sch Med, Div Pediat Surg, Pittsburgh, PA 15224 USA

[2] Univ Pittsburgh, Sch Med, Div Pathol, Pittsburgh, PA 15224 USA

[3] Univ Pittsburgh, Sch Med, Newborn Med Childrens Hosp Pittsburgh, Pittsburgh, PA 15224 USA

[4] Univ Pittsburgh, Sch Med, Dept Surg, Pittsburgh, PA 15224 USA

[5] Univ Pittsburgh, Sch Med, Dept Pediat, Pittsburgh, PA 15224 USA

[6] Univ Pittsburgh, Sch Med, Dept Pathol, Pittsburgh, PA 15224 USA

[7] Univ Cambridge, Addenbrookes Hosp, Dept Med, Div Gastroenterol & Hepatol, Cambridge CB2 0QQ, England

[8] Harvard Univ, Sch Med, Brigham & Womens Hosp, Div Gastroenterol Hepatol & Endoscopy,Dept Med, Boston, MA 02115 USA

来源：

JOURNAL OF BIOLOGICAL CHEMISTRY | 2014年 / 289卷 / 14期

基金：

美国国家卫生研究院;

关键词：

Inflammation; Innate Immunity; Necrotizing Enterocolitis; Sepsis; Toll-like Receptors (TLR); UNFOLDED PROTEIN RESPONSE; STEM-CELLS; ENTEROCYTE MIGRATION; ER STRESS; NITRIC-OXIDE; TLR4; PATHOGENESIS; CHOP; PROLIFERATION; EPITHELIUM;

D O I：

10.1074/jbc.M113.526517

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Background: Cellular cues that regulate intestinal stem cell (ISC) apoptosis are unknown. Results: Toll-like-receptor 4 (TLR4) activation on ISCs induces endoplasmic reticulum (ER) stress, leading to ISC apoptosis and necrotizing enterocolitis (NEC). Conclusion: TLR4-induced ER stress in ISCs leads to apoptosis and NEC. Significance: This is the first study revealing that ER stress in ISCs via immune receptors induces NEC. The cellular cues that regulate the apoptosis of intestinal stem cells (ISCs) remain incompletely understood, yet may play a role in diseases characterized by ISC loss including necrotizing enterocolitis (NEC). Toll-like receptor-4 (TLR4) was recently found to be expressed on ISCs, where its activation leads to ISC apoptosis through mechanisms that remain incompletely explained. We now hypothesize that TLR4 induces endoplasmic reticulum (ER) stress within ISCs, leading to their apoptosis in NEC pathogenesis, and that high ER stress within the premature intestine predisposes to NEC development. Using transgenic mice and cultured enteroids, we now demonstrate that TLR4 induces ER stress within Lgr5 (leucine-rich repeat-containing G-protein-coupled receptor 5)-positive ISCs, resulting in crypt apoptosis. TLR4 signaling within crypts was required, because crypt ER stress and apoptosis occurred in TLR4(IEC-OVER) mice expressing TLR4 only within intestinal crypts and epithelium, but not TLR4(IEC) mice lacking intestinal TLR4. TLR4-mediated ER stress and apoptosis of ISCs required PERK (protein kinase-related PKR-like ER kinase), CHOP (C/EBP homologous protein), and MyD88 (myeloid differentiation primary response gene 88), but not ATF6 (activating transcription factor 6) or XBP1 (X-box-binding protein 1). Human and mouse NEC showed high crypt ER stress and apoptosis, whereas genetic inhibition of PERK or CHOP attenuated ER stress, crypt apoptosis, and NEC severity. Strikingly, using intragastric delivery into fetal mouse intestine, prevention of ER stress reduced TLR4-mediated ISC apoptosis and mucosal disruption. These findings identify a novel link between TLR4-induced ER stress and ISC apoptosis in NEC pathogenesis and suggest that increased ER stress within the premature bowel predisposes to NEC development.

引用

页码：9584 / 9599

页数：16

共 39 条

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