title: Contribution of Ninjurin1 to Toll-like receptor 4 signaling and systemic inflammation.
abstract: Nerve injury-induced protein (Ninjurin [Ninj]) 1 is an adhesion molecule originally identified in Schwann cells after nerve injury, whereas it is also expressed in leukocytes, epithelium, endothelium, and various organs, and is induced under inflammatory conditions. Its contribution to inflammation was so far restricted to the nervous system and exclusively attributed to its role during leukocyte migration. We hypothesized a proinflammatory role for Ninj1 also outside the nervous system. To elucidate its impact during inflammation, we analyzed expression levels and its contribution to inflammation in septic mice and studied its effect on inflammatory signaling in vitro. The effect on inflammation was analyzed by genetic (only in vitro) and pharmacologic repression in septic mice (cecal ligation and puncture) and cell culture, respectively. Repression of Ninj1 by an inhibitory peptide or small interfering RNA attenuated LPS-triggered inflammation in macrophages and endothelial cells by modulating p38 phosphorylation and activator protein-1 activation. Inhibition of Ninj1 in septic mice reduced systemic and pulmonary inflammation as well as organ damage, and ameliorated survival after 24 hours. Ninj1 is elevated under inflammatory conditions and contributes to inflammation not only by mediating leukocyte migration, but also by modulating Toll-like receptor 4-dependent expression of inflammatory mediators. We assume that, owing to both mechanisms, inhibition reduces systemic inflammation and organ damage in septic mice. Our data contribute to a better understanding of the complex inflammatory mechanisms and add a novel therapeutic target for inflammatory conditions such as sepsis.
authors: 1 Department of Anesthesiology, Intensive Care Medicine, and Pain Therapy, University Hospital Frankfurt, Frankfurt am Main, Germany; and.
authors: Carla
authors: C
authors: Jennewein
authors: 1 Department of Anesthesiology, Intensive Care Medicine, and Pain Therapy, University Hospital Frankfurt, Frankfurt am Main, Germany; and.
authors: Ralf
authors: R
authors: Sowa
authors: 1 Department of Anesthesiology, Intensive Care Medicine, and Pain Therapy, University Hospital Frankfurt, Frankfurt am Main, Germany; and.
authors: Anne C
authors: AC
authors: Faber
authors: 1 Department of Anesthesiology, Intensive Care Medicine, and Pain Therapy, University Hospital Frankfurt, Frankfurt am Main, Germany; and.
authors: Madlen
authors: M
authors: Dildey
authors: 2 Institute of Biochemistry I, Faculty of Medicine, Goethe-University, Frankfurt am Main, Germany.
authors: Andreas
authors: A
authors: von Knethen
authors: 1 Department of Anesthesiology, Intensive Care Medicine, and Pain Therapy, University Hospital Frankfurt, Frankfurt am Main, Germany; and.
authors: Patrick
authors: P
authors: Meybohm
authors: 1 Department of Anesthesiology, Intensive Care Medicine, and Pain Therapy, University Hospital Frankfurt, Frankfurt am Main, Germany; and.
authors: Bertram
authors: B
authors: Scheller
authors: 1 Department of Anesthesiology, Intensive Care Medicine, and Pain Therapy, University Hospital Frankfurt, Frankfurt am Main, Germany; and.
authors: Stefan
authors: S
authors: Dröse
authors: 1 Department of Anesthesiology, Intensive Care Medicine, and Pain Therapy, University Hospital Frankfurt, Frankfurt am Main, Germany; and.
authors: Kai
authors: K
authors: Zacharowski
mesh_terms: D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics / Q000276:immunology*; D002465:Cell Movement / Q000187:drug effects; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008070:Lipopolysaccharides / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009414:Nerve Growth Factors / Q000235:genetics / Q000276:immunology*; D010766:Phosphorylation / Q000187:drug effects; D011070:Poly I-C / Q000494:pharmacology; D061251:Primary Cell Culture; D018805:Sepsis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction; D018746:Systemic Inflammatory Response Syndrome / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D013682:Teichoic Acids / Q000494:pharmacology; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000276:immunology*; D018808:Transcription Factor AP-1 / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D008070:Lipopolysaccharides; C484438:NINJ1 protein, human; D009414:Nerve Growth Factors; C484439:Ninj1 protein, mouse; D013682:Teichoic Acids; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; C009900:lipoteichoic acid; D048051:p38 Mitogen-Activated Protein Kinases; D011070:Poly I-C
keywords: Toll-like receptor; cecal ligation and puncture; signaling; systemic inflammatory response syndrome