| TLR9 and the NLRP3 Inflammasome Link Acinar Cell Death With Inflammation in Acute Pancreatitis. | |
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MedLine Citation:
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PMID: 21439959 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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BACKGROUND & AIMS: Acute pancreatitis is characterized by early activation of intracellular proteases followed by acinar cell death and inflammation. Activation of damage-associated molecular pattern (DAMP) receptors and a cytosolic complex termed the inflammasome initiates forms of inflammation. In this study, we examined whether DAMP-receptors and the inflammasome provide the link between cell death and the initiation of inflammation in pancreatitis. METHODS: Acute pancreatitis was induced by caerulein stimulation in wild-type mice and mice deficient in components of the inflammasome (ASC, NLRP3, caspase-1), Toll-like receptor 9 (TLR9), or the purinergic receptor P2X(7). Resident and infiltrating immune cell populations and pro-IL-1β expression were characterized in control and caerulein-treated adult murine pancreas. TLR9 expression was quantified in pancreatic cell populations. Additionally, wild-type mice were pretreated with a TLR9 antagonist prior to induction of acute pancreatitis by caerulein or retrograde bile duct infusion of taurolithocholic acid 3-sulfate (TLCS). RESULTS: Caspase-1, ASC, and NLPR3 were required for inflammation in acute pancreatitis. Genetic deletion of Tlr9 reduced pancreatic edema, inflammation, and pro-IL-1β expression in pancreatitis. TLR9 was expressed in resident immune cells of the pancreas, which are predominantly macrophages. Pretreatment with the TLR9 antagonist IRS954 reduced pancreatic edema, inflammatory infiltrate, and apoptosis. Pretreatment with IRS954 reduced pancreatic necrosis and lung inflammation in TLCS-induced acute pancreatitis. CONCLUSIONS: Components of the inflammasome, specifically ASC, caspase-1, and NLRP3, are required for the development of inflammation in acute pancreatitis. TLR9 and P2X(7) are important DAMP receptors upstream of inflammasome activation, and their antagonism could provide a new therapeutic strategy for treating acute pancreatitis. |
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Authors:
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Rafaz Hoque; Muhammad Sohail; Ahsan Malik; Sherhayar Sarwar; Yuhuan Luo; Ahsan Shah; Franck Barrat; Richard Flavell; Fred Gorelick; Sohail Husain; Wajahat Mehal |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2011-3-23 |
Journal Detail:
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Title: Gastroenterology Volume: - ISSN: 1528-0012 ISO Abbreviation: - Publication Date: 2011 Mar |
Date Detail:
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Created Date: 2011-3-28 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0374630 Medline TA: Gastroenterology Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved. |
Affiliation:
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Section of Digestive Diseases, Yale University, New Haven, CT, USA. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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