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

Afrazi, Amin; Branca, Maria F.; Sodhi, Chhinder P.; Good, Misty; Yamaguchi, Yoshiaki; Egan, Charlotte E.; Lü, Peng; Jia, Hongpeng; Shaffiey, Shahab; Lin, Joyce; Ma, Congrong; Vincent, Garret; Prindle, Thomas; Weyandt, Samantha; Neal, Matthew D.; Ozolek, John A.; Wiersch, John; Tschurtschenthaler, Markus; Shiota, Chiyo; Gittes, George K.; Billiar, Timothy R.; Mollen, Kevin P.; Kaser, Arthur; Blumberg, Richard S.; Hackam, David J.

doi:10.1074/jbc.m113.526517

Cited by 146 publications

(169 citation statements)

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“…Our results showed significantly decreased levels of apoptosis in the jejunum and ileum of irinotecan-treated BALB/c-Tlr4 -/-billy mice. This supports recent research suggesting that TLR4 signaling contributes to intestinal stem cell apoptosis through endoplasmic reticular stress-related mechanisms (37). We also saw levels of proliferation inversely parallel these changes in cellular dynamics.…”

Section: Discussionsupporting

confidence: 77%

Irinotecan-Induced Gastrointestinal Dysfunction and Pain Are Mediated by Common TLR4-Dependent Mechanisms

Wardill

Gibson

Sebille

et al. 2016

Molecular Cancer Therapeutics

115

124

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Strong epidemiological data indicate that chemotherapy-induced gut toxicity and pain occur in parallel, indicating common underlying mechanisms. We have recently outlined evidence suggesting that TLR4 signaling may contribute to both side effects. We therefore aimed to determine if genetic deletion of TLR4 improves chemotherapy-induced gut toxicity and pain. Forty-two female wild-type (WT) and 42 Tlr4 null (−/−) BALB/c mice weighing between 18 and 25 g (10–13 weeks) received a single 270 mg/kg (i.p.) dose of irinotecan hydrochloride or vehicle control and were killed at 6, 24, 48, 72, and 96 hours. Bacterial sequencing was conducted on cecal samples of control animals to determine the gut microbiome profile. Gut toxicity was assessed using validated clinical and histopathologic markers, permeability assays, and inflammatory markers. Chemotherapy-induced pain was assessed using the validated rodent facial grimace criteria, as well as immunologic markers of glial activation in the lumbar spinal cord. TLR4 deletion attenuated irinotecan-induced gut toxicity, with improvements in weight loss (P = 0.0003) and diarrhea (P < 0.0001). Crypt apoptosis was significantly decreased in BALB/c-Tlr4−/−billy mice (P < 0.0001), correlating with lower mucosal injury scores (P < 0.005). Intestinal permeability to FITC-dextran (4 kDa) and LPS translocation was greater in WT mice than in BALB/c-Tlr4−/−billy (P = 0.01 and P < 0.0001, respectively). GFAP staining in the lumbar spinal cord, indicative of astrocytic activation, was increased at 6 and 72 hours in WT mice compared with BALB/c-Tlr4−/−billy mice (P = 0.008, P = 0.01). These data indicate that TLR4 is uniquely positioned to mediate irinotecan-induced gut toxicity and pain, highlighting the possibility of a targetable gut/CNS axis for improved toxicity outcomes. Mol Cancer Ther; 15(6); 1376–86. ©2016 AACR.

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Section: Discussionsupporting

confidence: 77%

Irinotecan-Induced Gastrointestinal Dysfunction and Pain Are Mediated by Common TLR4-Dependent Mechanisms

Wardill

Gibson

Sebille

et al. 2016

Molecular Cancer Therapeutics

115

124

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“…Recent studies have highlighted such differences, such as those showing that intraepithelial T cell receptor γδ lymphocytes are decreased in surgical NEC specimens compared with appropriate controls [55], as are lamina propria T regulatory cells [56]. A key player in intestinal inflammation and the response to pathogens is TLR4, and recent work has shown that TLR4 signalling is important in the development of NEC [33,57,58,59]. Intriguingly, TLR4 signalling also links to other factors involved in the pathogenesis of NEC, such as the microcirculation [59] (see below).…”

Section: Pathogenesismentioning

confidence: 99%

Current Research on the Epidemiology, Pathogenesis, and Management of Necrotizing Enterocolitis

2017

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Despite decades of research on necrotizing enterocolitis, we still do not fully understand the pathogenesis of the disease, or how to prevent or how to treat it. However, as a result of recent significant advances in the microbiology, molecular biology, and cell biology of the intestine of preterm infants and infants with necrotizing enterocolitis, there is some hope that research into this devastating disease will yield some important translation into effective prevention, more rapid diagnosis, and novel therapies.

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“…It has been proved that UPR can cross-talk with inflammatory pathways at different levels, such as producing reactive oxygen species and activating NF-kB, JNK, and IRF3. [28][29][30][31][32] In this study, we found that the myocardial IRE1 branch robustly promoted NF-kBemediated proinflammatory cytokine production. Consistently, previous studies also reported that once activated, phosphorylated IRE1 was able to bind TRAF2, a member of the TRAF family, and led to subsequent IkB kinase activation and IkB degradation.…”

Section: Discussionmentioning

confidence: 88%

Endoplasmic Reticulum Stress Aggravates Viral Myocarditis by Raising Inflammation Through the IRE1-Associated NF-κB Pathway

Zha¹,

Yan²,

Dong

et al. 2015

Canadian Journal of Cardiology

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

Abstract: 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).

Cited by 146 publications

References 40 publications

Irinotecan-Induced Gastrointestinal Dysfunction and Pain Are Mediated by Common TLR4-Dependent Mechanisms

Irinotecan-Induced Gastrointestinal Dysfunction and Pain Are Mediated by Common TLR4-Dependent Mechanisms

Current Research on the Epidemiology, Pathogenesis, and Management of Necrotizing Enterocolitis

Endoplasmic Reticulum Stress Aggravates Viral Myocarditis by Raising Inflammation Through the IRE1-Associated NF-κB Pathway

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