Safe TNF-based antitumor therapy following p55TNFR reduction in intestinal epithelium

Hauwermeiren, Filip Van; Armaka, Marietta; Karagianni, Niki; Kranidioti, Ksanthi; Vandenbroucke, Roosmarijn E.; Loges, Sonja; Roy, Maarten Van; Staelens, Jan; Puimège, Leen; Palagani, Ajay; Berghe, Wim Vanden; Victoratos, Panayiotis; Carmeliet, Peter; Libert, Claude; Kollias, George

doi:10.1172/jci65624

Cited by 67 publications

(94 citation statements)

References 50 publications

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“…[45][46][47] In agreement with this and with previous results from our group, 48,49 we detected LPS-induced intestinal leakage of orally administered dextran and increased bacterial translocation to the MLNs. In addition, both EGF injection (which assures an optimal gut barrier function) and treatment with antibiotics (which removes all intestinal flora) resulted in protection against LPS-induced lethality and this was correlated with reduced intestinal permeability.…”

Section: Resultssupporting

confidence: 92%

Pro-inflammatory effects of matrix metalloproteinase 7 in acute inflammation

et al. 2014

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Matrix metalloproteinase 7 (MMP7) is a member of the MMP family. In the small intestine, MMP7 is responsible for activating α-defensins, which are broad-spectrum anti-microbial peptides produced by the Paneth cells. We report that MMP7(-/-) mice are resistant to LPS-induced lethality and that this resistance is correlated with reduced levels of systemic cytokines. LPS induced the upregulation and activation of MMP7 in the small intestine, degranulation of the Paneth cells, and induction of intestinal permeability in MMP7(+/+) mice. In MMP7(-/-) mice, both LPS-induced intestinal permeability and consequent bacterial translocation to the mesenteric lymph nodes were reduced. Based on gene expression analysis and evaluation of intestinal damage, we attribute the protected state of MMP7(-/-) mice to reduced intestinal inflammation. Interestingly, we found that different α-defensins, namely Crp1 (DEFA1) and Crp4 (DEFA4), can stimulate IL-6 release in macrophages and ileum explants in a TLR4 independent way. We conclude that absence of MMP7 protects mice from LPS-induced intestinal permeability and lethality, and suggest that MMP7-activated α-defensins, in addition to their previously recognized bactericidal and anti-inflammatory roles, may exhibit pro-inflammatory activities in the intestine by activating macrophages and amplifying the local inflammatory response in the gut, leading to intestinal leakage and subsequent increase in systemic inflammation.

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Section: Resultssupporting

confidence: 92%

Pro-inflammatory effects of matrix metalloproteinase 7 in acute inflammation

et al. 2014

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“…For instance, studies have demonstrated that APAP‐induced liver injury results in the release of inflammatory and cytotoxic cytokines, such as TNFα and high‐mobility group box 1 (HMGB1), into the serum . TNFα itself has been shown to play a role in inducing intestinal injury and increasing intestinal permeability in various disease models . For these reasons, we first focused on investigating potential roles of TNFα signaling in APAP‐induced intestinal toxicity.…”

Section: Resultsmentioning

confidence: 99%

Acetaminophen Intoxication Rapidly Induces Apoptosis of Intestinal Crypt Stem Cells and Enhances Intestinal Permeability

et al. 2019

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Acetaminophen (APAP)‐induced liver injury is the most common cause of acute liver failure (ALF) in the Western world. APAP toxicity progresses to multiorgan dysfunction and thus has broader whole‐body implications. Importantly, greater 30‐day mortality has been observed in liver transplant recipients following ALF due to APAP‐related versus non‐APAP‐related causes. Reasons for this discrepancy have yet to be determined. Extrahepatic toxicities of APAP overdose may represent underappreciated and unaddressed comorbidities within this patient population. In the present study, rapid induction of apoptosis following APAP overdose was observed in the intestine, an organ that greatly influences the physiology of the liver. Strikingly, apoptotic cells appeared to be strictly restricted to the intestinal crypts. The use of leucine‐rich repeat‐containing G protein–coupled receptor 5 (LGR5) reporter mice confirmed that the LGR5‐positive (+) crypt base stem cells were disproportionately affected by APAP‐induced cell death. Although the apoptotic cells were cleared within 24 hours after APAP treatment, potentially long‐lived consequences on the intestine due to APAP exposure were indicated by prolonged deficits in gut barrier function. Moreover, small intestinal cell death was found to be independent of tumor necrosis factor receptor signaling and may represent a direct toxic insult to the intestine by exposure to high concentrations of APAP. Conclusion: APAP induces intestinal injury through a regulated process of apoptotic cell death that disproportionately affects LGR5+ stem cells. This work advances our understanding of the consequences of APAP toxicity in a novel organ that was not previously considered as a significant site of injury and thus presents potential new considerations for patient management.

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“…The following mouse lines were used in this study: AlfpCre, 31 NEMO floxed, 10 FADD floxed, 32 Tnf À / À , 23 33 TRAIL-R floxed, 34 Fas floxed 35 and Rag1 À / À . 36 All mice were maintained in C57BL/6 background.…”

Section: Methodsmentioning

confidence: 99%

Death receptor-independent FADD signalling triggers hepatitis and hepatocellular carcinoma in mice with liver parenchymal cell-specific NEMO knockout

et al. 2014

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Hepatocellular carcinoma (HCC) usually develops in the context of chronic hepatitis triggered by viruses or toxic substances causing hepatocyte death, inflammation and compensatory proliferation of liver cells. Death receptors of the TNFR superfamily regulate cell death and inflammation and are implicated in liver disease and cancer. Liver parenchymal cell-specific ablation of NEMO/IKKc, a subunit of the IjB kinase (IKK) complex that is essential for the activation of canonical NF-jB signalling, sensitized hepatocytes to apoptosis and caused the spontaneous development of chronic hepatitis and HCC in mice. Here we show that hepatitis and HCC development in NEMO LPC-KO mice is triggered by death receptor-independent FADD-mediated hepatocyte apoptosis. TNF deficiency in all cells or conditional LPC-specific ablation of TNFR1, Fas or TRAIL-R did not prevent hepatocyte apoptosis, hepatitis and HCC development in NEMO LPC-KO mice. To address potential functional redundancies between death receptors we generated and analysed NEMO LPC-KO mice with combined LPC-specific deficiency of TNFR1, Fas and TRAIL-R and found that also simultaneous lack of all three death receptors did not prevent hepatocyte apoptosis, chronic hepatitis and HCC development. However, LPC-specific combined deficiency in TNFR1, Fas and TRAIL-R protected the NEMOdeficient liver from LPS-induced liver failure, showing that different mechanisms trigger spontaneous and LPS-induced hepatocyte apoptosis in NEMO LPC-KO mice. In addition, NK cell depletion did not prevent liver damage and hepatitis. Moreover, NEMO LPC-KO mice crossed into a RAG-1-deficient genetic background-developed hepatitis and HCC. Collectively, these results show that the spontaneous development of hepatocyte apoptosis, chronic hepatitis and HCC in NEMO LPC-KO mice occurs independently of death receptor signalling, NK cells and B and T lymphocytes, arguing against an immunological trigger as the critical stimulus driving hepatocarcinogenesis in this model.

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Safe TNF-based antitumor therapy following p55TNFR reduction in intestinal epithelium

Cited by 67 publications

References 50 publications

Pro-inflammatory effects of matrix metalloproteinase 7 in acute inflammation

Pro-inflammatory effects of matrix metalloproteinase 7 in acute inflammation

Acetaminophen Intoxication Rapidly Induces Apoptosis of Intestinal Crypt Stem Cells and Enhances Intestinal Permeability

Death receptor-independent FADD signalling triggers hepatitis and hepatocellular carcinoma in mice with liver parenchymal cell-specific NEMO knockout

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