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Natterin an aerolysin-like fish toxin drives IL-1β-dependent neutrophilic inflammation mediated by caspase-1 and caspase-11 activated by the inflammasome sensor NLRP6
International Immunopharmacology ( IF 4.8 ) Pub Date : 2020-12-27 , DOI: 10.1016/j.intimp.2020.107287
Carla Lima 1 , Maria Alice Pimentel Falcao 1 , Aline Ingrid Andrade-Barros 1 , Ana Carolina Seni-Silva 1 , Lidiane Zito Grund 1 , Eniko Balogh 2 , Katia Conceiçao 3 , Valerie F Queniaux 4 , Bernhard Ryffel 4 , Monica Lopes-Ferreira 1
Affiliation  

Natterin is an aerolysin-like pore-forming toxin responsible for the toxic effects of the venom of the medically significant fish Thalassophryne nattereri. Using a combination of pharmacologic and genetic loss-of-function approaches we conduct a systematic investigation of the regulatory mechanisms that control Natterin-induced neutrophilic inflammation in the peritonitis model. Our data confirmed the capacity of Natterin to induce a strong and sustained neutrophilic inflammation leading to systemic inflammatory lung infiltration and revealed overlapping regulatory paths in its control. We found that Natterin induced the extracellular release of mature IL-1β and the sustained production of IL-33 by bronchial epithelial cells. We confirmed the dependence of both ST2/IL-33 and IL-17A/IL-17RA signaling on the local and systemic neutrophils migration, as well as the crucial role of IL-1α, caspase-1 and caspase-11 for neutrophilic inflammation. The inflammation triggered by Natterin was a gasdermin-D-dependent inflammasome process, despite the cells did not die by pyroptosis. Finally, neutrophilic inflammation was mediated by non-canonical NLRP6 and NLRC4 adaptors through ASC interaction, independent of NLRP3. Our data highlight that the inflammatory process dependent on non-canonical inflammasome activation can be a target for pharmacological intervention in accidents by T. nattereri, which does not have adequate specific therapy.



中文翻译:


Natterin 是一种类似气溶素的鱼毒素,可驱动由炎症小体传感器 NLRP6 激活的 caspase-1 和 caspase-11 介导的 IL-1β 依赖性中性粒细胞炎症



Natterin 是一种类似气溶素的成孔毒素,导致具有医学意义的鱼类Thalassophryne nattereri的毒液产生毒性作用。通过结合药理学和遗传功能丧失方法,我们对腹膜炎模型中控制 Natterin 诱导的中性粒细胞炎症的调节机制进行了系统研究。我们的数据证实了 Natterin 诱导强烈且持续的中性粒细胞炎症的能力,导致全身炎症性肺部浸润,并揭示了其控制中重叠的调节路径。我们发现 Natterin 诱导成熟 IL-1β 的胞外释放以及支气管上皮细胞持续产生 IL-33。我们证实了 ST2/IL-33 和 IL-17A/IL-17RA 信号传导对局部和全身中性粒细胞迁移的依赖性,以及 IL-1α、caspase-1 和 caspase-11 在中性粒细胞炎症中的关键作用。 Natterin 引发的炎症是 Gasdermin-D 依赖性炎症小体过程,尽管细胞并未因焦亡而死亡。最后,中性粒细胞炎症是由非经典 NLRP6 和 NLRC4 接头通过 ASC 相互作用介导的,独立于 NLRP3。我们的数据强调,依赖于非典型炎症体激活的炎症过程可以成为T. nattereri事故中药物干预的目标,而 T. nattereri 没有足够的特异性治疗。

更新日期:2020-12-27
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