Mechanisms of NLRP3 inflammasome activation and its role in NSAID-induced enteropathy

Mucosal Immunology
Akira HigashimoriTetsuo Arakawa

Abstract

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 a...Continue Reading

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Nov 14, 2019·Current Gastroenterology Reports·Carmelo Scarpignato, Ingvar Bjarnason
Jul 31, 2019·Journal of Gastroenterology and Hepatology·Hirotaka FuruhashiRyota Hokari
Sep 13, 2020·Journal of Gastroenterology and Hepatology·Akira HigashimoriYasuhiro Fujiwara
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Oct 16, 2021·Journal of Molecular Biology·Yinan WeiZhenyu Li

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