Abstract
NLRP3 inflammasome is a key component of the inflammatory process and its dysregulation contributes to IBD for its ability to induce IL-1β release. Previously, we reported that a novel small molecular activator of Nrf2, 3-(2-oxo-2-phenylethylidene)-2,3,6,7-tetrahydro-1H-pyrazino-[2,1-a]isoquinolin-4(11bH)-one (compound 1) can prevent the development of colorectal adenomas in AOM-DSS models. Here we further investigated the anti-inflammatory effect of compound 1 in DSS-induced colitis in C57BL/6 and NLRP3(-/-) mice, and revealed the possible modulation by compound 1 of NLRP3 inflammasome-mediated IL-1β release from macrophages. In C57BL/6 mice, oral administration of compound 1 significantly attenuated DSS-induced colonic pathological damage, remarkably inhibited inflammatory cells infiltration and decreased myeloperoxidase (MPO) and IL-1β secretion in colons. In contrast, mice deficient for NLRP3 were less sensitive to DSS-induced acute colitis, and compound 1 treatment exerted no protective effect on DSS-induced intestinal inflammation in NLRP3(-/-) mice. The protective effect of compound 1 may be attributed to its inhibition of NLRP3 inflammasome and Nrf2 activation in colons. Furthermore, compound 1, as a small molecular activator of Nrf2, significantly inhibited NLRP3 inflammasome activation in both THP-1 derived macrophages and bone-marrow derived macrophages, as indicated by reduced expression of NLRP3 and cleaved caspase-1, and lowered IL-1β secretion. Finally, compound 1-induced NLRP3 inflammasome inhibition is through blocking NLRP3 priming step and dependent on Nrf2 activation. Taken together, our findings demonstrate that compound 1 might be a potential agent for the treatment of IBD by targeting Nrf2 and NLRP3 inflammasome.
Keywords:
DSS; Inflammatory bowel disease; NLRP3 inflammasome; Nrf2; ROS.
Copyright © 2015 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Anti-Inflammatory Agents, Non-Steroidal / administration & dosage
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Anti-Inflammatory Agents, Non-Steroidal / pharmacology
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Anti-Inflammatory Agents, Non-Steroidal / therapeutic use*
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Antioxidant Response Elements / drug effects*
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Carrier Proteins / antagonists & inhibitors*
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Carrier Proteins / metabolism
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Cell Line
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Cells, Cultured
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Colitis, Ulcerative / immunology
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Colitis, Ulcerative / metabolism
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Colitis, Ulcerative / pathology
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Colitis, Ulcerative / prevention & control*
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Colon / drug effects
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Colon / immunology
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Colon / metabolism
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Colon / pathology
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Dose-Response Relationship, Drug
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Female
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Gastrointestinal Agents / administration & dosage
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Gastrointestinal Agents / pharmacology
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Gastrointestinal Agents / therapeutic use
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Genes, Reporter / drug effects
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Humans
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Inflammasomes / drug effects*
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Inflammasomes / metabolism
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Intestinal Mucosa / drug effects
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Intestinal Mucosa / immunology
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Intestinal Mucosa / metabolism
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Intestinal Mucosa / pathology
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Isoquinolines / administration & dosage
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Isoquinolines / pharmacology
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Isoquinolines / therapeutic use*
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Macrophages / drug effects
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Macrophages / immunology
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Macrophages / metabolism
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Macrophages / pathology
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Male
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Mice, Inbred C57BL
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Mice, Knockout
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NF-E2-Related Factor 2 / agonists*
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NF-E2-Related Factor 2 / antagonists & inhibitors
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NF-E2-Related Factor 2 / genetics
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NF-E2-Related Factor 2 / metabolism
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NLR Family, Pyrin Domain-Containing 3 Protein
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Pyrazines / administration & dosage
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Pyrazines / pharmacology
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Pyrazines / therapeutic use*
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RNA Interference
Substances
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3-(2-oxo-2-phenylethylidene)-2,3,6,7-tetrahydro-1H-pyrazino(2,1-a)isoquinolin-4(11bH)-one
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Anti-Inflammatory Agents, Non-Steroidal
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Carrier Proteins
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Gastrointestinal Agents
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Inflammasomes
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Isoquinolines
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NF-E2-Related Factor 2
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NFE2L2 protein, human
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NLR Family, Pyrin Domain-Containing 3 Protein
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Nlrp3 protein, mouse
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Pyrazines