Mechanisms of NLRP3 inflammasome activation and its role in NSAID-induced enteropathy.
Nonsteroidal anti-inflammatory drugs (NSAIDs) induce cytokines, including tumor necrosis factor-α and interleukins (ILs), in the small intestine via a Toll-like receptor 4 (TLR4)-dependent pathway, leading to intestinal ulceration. Activation of the inflammasome promotes pro-caspase-1 cleavage, leading to pro-IL-1β maturation. We examined the role of NLRP3 inflammasome in NSAID-induced enteropathy. Small intestinal damage developed 3 h after indomethacin administration, accompanied by increases in IL-1β and NLRP3 mRNA expression and mature caspase-1 and IL-1β levels. In vivo blocking of IL-1β using neutralizing antibodies attenuated indomethacin-induced damage, whereas exogenous IL-1β aggravated it. NLRP3(-/-) and caspase-1(-/-) mice exhibited resistance to the damage with reduction of mature IL-1β production. This resistance was abolished by exogenous IL-1β. TLR4 deficiency prevented intestinal damage and inhibited upregulation of NLRP3 and IL-1β mRNAs and maturation of pro-caspase-1 and pro-IL-1β, whereas TLR4 activation by its agonists exerted opposite effects. Apyrase, an adenosine triphosphate (ATP) scavenger, or Brilliant Blue G, a purinergic P2X7 receptor antagonist, inhibited the damage as well as caspase-1 activation and IL-1β processing, despite there being sufficient amounts of pro-IL-1β and NLRP3. These results suggest that NLRP3 inflammasome-derived IL-1β plays a crucial role in NSAID-induced enteropathy and that both TLR4- and P2X7-dependent pathways are required for NLRP3 inflammasome activation.
Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan.
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Higashimori
Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan.
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Watanabe
Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan.
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Nadatani
Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan.
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Takeda
Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan.
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Otani
Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan.
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Tanigawa
Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan.
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Yamagami
Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan.
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Shiba
Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan.
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Tominaga
Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan.
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Fujiwara
Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan.
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Arakawa
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D007213:Indomethacin; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism*; D007421:Intestine, Small / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000235:genetics / Q000378:metabolism*; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000378:metabolism*; D014456:Ulcer / Q000139:chemically induced / Q000276:immunology*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D058486:Receptors, Purinergic P2X7; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D020170:Caspase 1; D007213:Indomethacin