Loss of TLR3 and its downstream signaling accelerates acinar cell damage in the acute phase of pancreatitis

Regel, Ivonne; Raulefs, Susanne; Benitz, Simone; Mihaljevic, Charlotte; Rieder, Simon; Leinenkugel, Georg; Steiger, Katja; Schlitter, Anna Melissa; Esposito, Irene; Mayerle, Julia; Kong, Bo; Kleeff, Jörg und Michalski, Christoph W. (2019): Loss of TLR3 and its downstream signaling accelerates acinar cell damage in the acute phase of pancreatitis. In: Pancreatology, Bd. 19, Nr. 1: S. 149-157

Abstract

Background: Acute pancreatitis is accompanied by acinar cell damage releasing potential toll-like receptor 3 (TLR3) ligands. So far, TLR3 is known as a pattern recognition receptor in the immune signaling cascade triggering a type I interferon response. In addition, TLR3 signaling contributes to programmed cell death through the activation of caspase 8. However, the functional role of TLR3 and its downstream toll-like receptor adaptor molecule 1 (TICAM1) in the inflamed pancreas is unknown. Methods: To uncover the role of TLR3 signaling in acute pancreatitis, we induced a cerulein-mediated pancreatitis in Tlr3 and Ticam1 knockout (KO) mice and in wildtype animals. The exocrine damage was determined by blood serum analysis and histological examination. Immunohistochemistry, gene expression and immunoblot analysis were conducted to study TLR3 function. Results: After the induction of an acute pancreatitis, wildtype mice showed a high endosomal TLR3 expression in acinar cells. In comparison to wildtype and Ticam1 KO mice, Tlr3 KO mice exhibited the highest severity of pancreatitis with an increased NF-kappa B activation and elevated expression of the pro-inflammatory cytokines Il6 and Tnf, although the amount of infiltrating immune cells was unaffected. Additionally, we detected a strong elevation of acinar cell necrosis and reduced levels of cleaved caspase 8 in Tlr3 and Ticam1 KO mice. Conclusions: TLR3 and its downstream adaptor TICAM1 are important mediators of acinar cell damage in acute pancreatitis. They possess a critical role in programmed cell death and our data suggest that TLR3 signaling controls the onset and severity of acute pancreatitis. (C) 2018 IAP and EPC. Published by Elsevier B.V. All rights reserved.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1424-3903
• Sprache: Englisch