Higashimori A, Watanabe T, Nadatani Y, Takeda S, Otani K, Tanigawa T, Yamagami H, Shiba M, Tominaga K, Fujiwara Y, Arakawa T
Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan.
Mucosal Immunol. 2016 May;9(3):659-68. doi: 10.1038/mi.2015.89. Epub 2015 Sep 9.
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.
非甾体抗炎药（NSAIDs）通过Toll样受体4（TLR4）依赖性途径在小肠中诱导细胞因子，包括肿瘤坏死因子-α和白细胞介素（ILs），从而导致肠道溃疡。炎性小体的激活促进前半胱天冬酶-1的切割，导致前IL-1β成熟。我们研究了NLRP3炎性小体在NSAIDs诱导的肠病中的作用。吲哚美辛给药后3小时出现小肠损伤，同时伴有IL-1β和NLRP3 mRNA表达增加以及成熟的半胱天冬酶-1和IL-1β水平升高。使用中和抗体在体内阻断IL-1β可减轻吲哚美辛诱导的损伤，而外源性IL-1β则会加重损伤。NLRP3（-/-）和半胱天冬酶-1（-/-）小鼠对损伤表现出抗性，成熟IL-1β的产生减少。外源性IL-1β消除了这种抗性。TLR4缺陷可预防肠道损伤，并抑制NLRP3和IL-1β mRNA的上调以及前半胱天冬酶-1和前IL-1β的成熟，而其激动剂对TLR4的激活则产生相反的效果。尽管存在足够量的前IL-1β和NLRP3，但三磷酸腺苷双磷酸酶（一种三磷酸腺苷（ATP）清除剂）或亮蓝G（一种嘌呤能P2X7受体拮抗剂）可抑制损伤以及半胱天冬酶-1的激活和IL-1β的加工。这些结果表明，NLRP3炎性小体衍生的IL-1β在NSAIDs诱导的肠病中起关键作用，并且TLR4和P2X7依赖性途径都是NLRP3炎性小体激活所必需的。
