Dataset Information

NOD-Like Receptor Signaling in Cholesteatoma.

ABSTRACT: Background. Cholesteatoma is a destructive process of the middle ear resulting in erosion of the surrounding bony structures with consequent hearing loss, vestibular dysfunction, facial paralysis, or intracranial complications. The etiopathogenesis of cholesteatoma is controversial but is associated with recurrent ear infections. The role of intracellular innate immune receptors, the NOD-like receptors, and their associated signaling networks was investigated in cholesteatoma, since mutations in NOD-like receptor-related genes have been implicated in other chronic inflammatory disorders. Results. The expression of NOD2 mRNA and protein was significantly induced in cholesteatoma compared to the external auditory canal skin, mainly located in the epithelial layer of cholesteatoma. Microarray analysis showed significant upregulation for NOD2, not for NOD1, TLR2, or TLR4 in cholesteatoma. Moreover, regulation of genes in an interaction network of the NOD-adaptor molecule RIPK2 was detected. In addition to NOD2, NLRC4, and PYCARD, the downstream molecules IRAK1 and antiapoptotic regulator CFLAR showed significant upregulation, whereas SMAD3, a proapoptotic inducer, was significantly downregulated. Finally, altered regulation of inflammatory target genes of NOD signaling was detected. Conclusions. These results indicate that the interaction of innate immune signaling mediated by NLRs and their downstream target molecules is involved in the etiopathogenesis and growth of cholesteatoma.

SUBMITTER: Leichtle A

PROVIDER: S-EPMC4398947 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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NOD-Like Receptor Signaling in Cholesteatoma.

Leichtle Anke A Klenke Christin C Ebmeyer Joerg J Daerr Markus M Bruchhage Karl-Ludwig KL Hoffmann Anna Sophie AS Ryan Allen F AF Wollenberg Barbara B Sudhoff Holger H

BioMed research international 20150402

Background. Cholesteatoma is a destructive process of the middle ear resulting in erosion of the surrounding bony structures with consequent hearing loss, vestibular dysfunction, facial paralysis, or intracranial complications. The etiopathogenesis of cholesteatoma is controversial but is associated with recurrent ear infections. The role of intracellular innate immune receptors, the NOD-like receptors, and their associated signaling networks was investigated in cholesteatoma, since mutations in ...[more]

PMID: 25922834

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Project description:BackgroundLiver injury is a common and important clinical issue of severe heat stress (HS), which has toxic effects and promotes subsequent multiple organ failure. The pathogenesis of HS-induced liver injury has not been fully elucidated. Passively injured hepatocytes also drive liver injury. Exosomes, extracellular vesicles secreted by hepatocytes as "danger signals," mediate the intercellular transportation of diverse functional protein cargoes and modulate the biological processes of target cells. However, whether hepatocyte exosomes are involved in HS-induced liver injury has not been reported. The purpose of the current study was to clarify the release of hepatocyte exosomes under HS conditions and to explore their role in mediating HS-induced liver injury.MethodsHS was induced in hepatocytes or mice by hyperthermic treatment at 43.0 °C for 1 h. Exosomes from control and HS-exposed hepatocytes were isolated by standard differential ultracentrifugation. The hepatocyte exosomes were characterized, and the differentially expressed proteins of the control and HS exosomes were identified by isobaric tags for relative and absolute quantitation (iTRAQ) mass spectrometry and subjected to Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis. Recipient hepatocytes were treated with control or HS exosomes, whereas in vivo, the exosomes were infused into mice. The internalization of HS hepatocyte exosomes by hepatocytes or the liver was tracked. The effect of HS exosomes on the activation of the NOD-like receptor signaling pathway and liver injury was demonstrated in vitro and in vivo.ResultsHS induced an increase in the release of exosomes from hepatocytes, which were internalized by recipient liver cells in vitro and taken up by the liver in vivo. HS significantly changed the proteomic profiles of hepatocyte exosomes based on the iTRAQ analysis. The KEGG pathway analysis revealed the enrichment of proteins associated with injury and inflammatory signaling pathways, especially the NOD-like receptor signaling pathway, the activity of which was upregulated. Subsequently, the capacity of HS hepatocyte exosomes to activate the NOD-like receptor signaling pathway was verified and found to aggrevate liver damage and inflammation in vitro and in vivo.ConclusionsThis study is the first preliminary study to demonstrate the induction of acute liver injury by hepatic exosomes in the setting of severe HS and reveals potentially related pathways. These results provide a basis for future research and the identification of new targets for clinical intervention.

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NOD-Like Receptor Signaling in Cholesteatoma.

Publications

NOD-Like Receptor Signaling in Cholesteatoma.

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