TLR9 and the NLRP3 inflammasome link acinar cell death with inflammation in acute pancreatitis.

Abstract

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 initiate 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 (apoptosis-associated speck-like protein containing a caspase recruitment domain [ASC], NLRP3, caspase-1), Toll-like receptor 9 (TLR9), or the purinergic receptor P2X(7). Resident and infiltrating immune cell populations and pro-interleukin-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 before induction of acute pancreatitis by caerulein or retrograde bile duct infusion of taurolithocholic acid 3-sulfate.

RESULTS:

Caspase-1, ASC, and NLRP3 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 taurolithocholic acid 3-sulfate-induced acute pancreatitis.

CONCLUSIONS:

Components of the inflammasome, 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.

• Authors: Rafaz Hoque, Muhammad Sohail, Ahsan Malik, Sherhayar Sarwar, Yuhuan Luo, Ahsan Shah, Franck Barrat, Richard Flavell, Fred Gorelick, Sohail Husain, Wajahat Mehal
• Journal: Gastroenterology (Gastroenterology) Vol. 141 Issue 1 Pg. 358-69 (Jul 2011) ISSN: 1528-0012 [Electronic] United States
• PMID: 21439959 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• Anti-Inflammatory Agents
• Apoptosis Regulatory Proteins
• CARD Signaling Adaptor Proteins
• Carrier Proteins
• Cytoskeletal Proteins
• IRS 954
• Inflammasomes
• Interleukin-1
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Protein Precursors
• Purinergic P2X Receptor Antagonists
• Pycard protein, mouse
• RNA, Messenger
• Receptors, Purinergic P2X7
• Tlr9 protein, mouse
• Toll-Like Receptor 9
• interleukin 1 precursor
• taurolithocholic acid 3-sulfate
• Taurolithocholic Acid
• Ceruletide
• DNA
• Caspase 1

Topics

• Acute Disease
• Animals
• Anti-Inflammatory Agents (pharmacology)
• Apoptosis
• Apoptosis Regulatory Proteins
• CARD Signaling Adaptor Proteins
• Carrier Proteins (genetics, metabolism)
• Caspase 1 (genetics, metabolism)
• Ceruletide
• Cytoskeletal Proteins (genetics, metabolism)
• DNA (pharmacology)
• Disease Models, Animal
• Inflammasomes (deficiency, genetics, metabolism)
• Interleukin-1 (metabolism)
• Macrophages (immunology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• NLR Family, Pyrin Domain-Containing 3 Protein
• Necrosis
• Neutrophil Infiltration
• Pancreas (drug effects, immunology, pathology)
• Pancreatitis (chemically induced, genetics, immunology, pathology, prevention & control)
• Pneumonia (immunology, prevention & control)
• Protein Precursors (metabolism)
• Purinergic P2X Receptor Antagonists (pharmacology)
• RNA, Messenger (metabolism)
• Receptors, Purinergic P2X7 (genetics, metabolism)
• Severity of Illness Index
• Signal Transduction (drug effects)
• Taurolithocholic Acid (analogs & derivatives)
• Toll-Like Receptor 9 (antagonists & inhibitors, deficiency, genetics, metabolism)