Central role of the TIR‐domain‐containing adaptor‐inducing interferon‐β (TRIF) adaptor protein in murine sterile liver injury

Brempelis, Katherine J.; Yuen, Sebastian; Schwarz, Nicole; Mohar, Isaac

doi:10.1002/hep.29078

Cited by 12 publications

(10 citation statements)

References 52 publications

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“…Hepatocyte death is a central mechanism involved in both pathogen‐ and sterile injury‐induced pathologies and contributes to the development of liver disease . The efficient clearance of dead cells is a critical liver function to maintain tissue homeostasis.…”

Section: Discussionmentioning

confidence: 99%

Mannan-binding lectin deficiency exacerbates sterile liver injury in mice through enhancing hepatic neutrophil recruitment

Zhou

et al. 2018

Journal of Leukocyte Biology

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Noninfectious liver injury, including the effects of drugs and diet, is a major cause of liver diseases worldwide. The innate inflammatory response to hepatocyte death plays a crucial role in the outcome of liver injury. Mannan-binding lectin (MBL) is a pattern recognition molecule of the innate immune system, which is primarily produced by liver. MBL deficiency occurs with high frequency in the population and is reported associated with predisposition to infectious diseases. We here observed that genetic MBL ablation strongly sensitizes mice to sterile liver injury induced by carbon tetrachloride (CCl 4 ). Aggravated liver damage was shown in CCl 4 -administrated MBL −/− mice, as evidenced by severe hepatocyte death, elevated serum alanine aminotransferase and lactate dehydrogenase activity, and enhanced production of inflammatory cytokines. Mechanistic studies established that MBL deficiency caused increased chemokine CXCL2 production from liver macrophages upon CCl 4 stimulation, thereby promoting the hepatic recruitment of neutrophils and subsequent liver damage. Furthermore, MBL-mediated protection from CCl 4induced liver injury was validated by administration of an MBL-expressing liver-specific adenoassociated virus, which effectively ameliorated the hepatic damage in CCl4-treated MBL -/mice.We propose that MBL may be exploited as a new therapeutic approach in the treatment of chemical-induced sterile liver injury in patients with MBL deficiency. K E Y W O R D Scarbon tetrachloride, CXCL2, mannan-binding lectin, neutrophil, sterile liver injury

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Section: Discussionmentioning

confidence: 99%

Mannan-binding lectin deficiency exacerbates sterile liver injury in mice through enhancing hepatic neutrophil recruitment

Zhou

et al. 2018

Journal of Leukocyte Biology

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“…A pre-amplification step was included before the multiplex qRT-PCR assay (Brempelis et al, 2017), which included PCR reactions of cDNA as templates, and a primer mixture of TaqMan assays of interest (Thermo Fisher Scientific, Waltham, MA, USA) and the BIO-X-ACT Short Mix reagents (Bioline USA Inc., Taunton, MA, USA). The pre-amplified samples were diluted five-fold with RNase- and DNase-free H 2 O.…”

Section: Methodsmentioning

confidence: 99%

Precision-cut human liver slice cultures as an immunological platform

Roberto

Knupp

et al. 2018

Journal of Immunological Methods

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The liver is the central metabolic organ in the human body, and also plays an essential role in innate and adaptive immunity. While mouse models offer significant insights into immune-inflammatory liver disease, human immunology differs in important respects. It is not easy to address those differences experimentally. Therefore, to improve the understanding of human liver immunobiology and pathology, we have established precision-cut human liver slices to study innate immunity in human tissue. Human liver slices collected from resected livers could be maintained in ex vivo culture over a two-week period. Although an acute inflammatory response accompanied by signs of tissue repair was observed in liver tissue following slicing, the expression of many immune genes stabilized after day 4 and remained stable until day 15. Remarkably, histological evidence of pre-existing liver diseases was preserved in the slices for up to 7 days. Following 7 days of culture, exposure of liver slices to the toll-like receptor (TLR) ligands, TLR3 ligand Poly-I:C and TLR4 ligand LPS, resulted in a robust activation of acute inflammation and cytokine genes. Moreover, Poly-I:C treatment induced a marked antiviral response including increases of interferons IFNB, IL-28B and a group of interferon-stimulated genes. Therefore, precision-cut liver slices emerge as a valuable tool to study human innate immunity.

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“…In the non Myd88-dependent pathway, TLR4 triggers the activation of the TRIF-related adaptor molecule (TRAM), followed by the activation of interferon regulatory factor 3, which induces the production of IFN-γ. In the later inflammatory response process, TRAM can also activate NF-κB, inducing inflammatory factor expression and activation (Brempelis et al, 2017 ; Yan et al, 2017 ).…”

Section: Introductionmentioning

confidence: 99%

Toll-Like Receptor 4 Mediates Methamphetamine-Induced Neuroinflammation through Caspase-11 Signaling Pathway in Astrocytes

Qiao

Chen

et al. 2017

Front. Mol. Neurosci.

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Methamphetamine (METH) is an amphetamine-typed stimulant drug that is increasingly being abused worldwide. Previous studies have shown that METH toxicity is systemic, especially targeting dopaminergic neurons in the central nervous system (CNS). However, the role of neuroinflammation in METH neurotoxicity remains unclear. We hypothesized that Toll-like receptor 4 (TLR4) and Caspase-11 are involved in METH-induced astrocyte-related neuroinflammation. We tested our hypothesis by examining the changes of TLR4 and Caspase-11 protein expression in primary cultured C57BL/6 mouse astrocytes and in the midbrain and striatum of mice exposed to METH with western blot and double immunofluorescence labeling. We also determined the effects of blocking Caspase-11 expression with wedelolactone (a specific inhibitor of Caspase-11) or siRNA on METH-induced neuroinflammation in astrocytes. Furthermore, we determined the effects of blocking TLR4 expression with TAK-242 (a specific inhibitor of TLR4) or siRNA on METH-induced neuroinflammation in astrocytes. METH exposure increased Caspase-11 and TLR4 expression both in vitro and in vivo, with the effects in vitro being dose-dependent. Inhibition of Caspase-11 expression with either wedelolactone or siRNAs reduced the expression of inflammasome NLRP3 and pro-inflammatory cytokines. In addition, blocking TLR4 expression inhibited METH-induced activation of NF-κB and Caspase-11 in vitro and in vivo, suggesting that TLR4-Caspase-11 pathway is involved in METH-induced neuroinflammation. These results indicate that Caspase-11 and TLR4 play an important role in METH-induced neuroinflammation and may be potential gene targets for therapeutics in METH-caused neurotoxicity.

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Central role of the TIR‐domain‐containing adaptor‐inducing interferon‐β (TRIF) adaptor protein in murine sterile liver injury

Cited by 12 publications

References 52 publications

Mannan-binding lectin deficiency exacerbates sterile liver injury in mice through enhancing hepatic neutrophil recruitment

Mannan-binding lectin deficiency exacerbates sterile liver injury in mice through enhancing hepatic neutrophil recruitment

Precision-cut human liver slice cultures as an immunological platform

Toll-Like Receptor 4 Mediates Methamphetamine-Induced Neuroinflammation through Caspase-11 Signaling Pathway in Astrocytes

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