Opposing roles of LTB4 and PGE2 in regulating the inflammasome-dependent scorpion venom-induced mortality.
Opposing roles of LTB4 and PGE2 in regulating the inflammasome-dependent scorpion venom-induced mortality.
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DOI：
10.1038/ncomms10760
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发表时间：
2016-02-23
影响因子：
16.6
通讯作者：
Faccioli LH
中科院分区：
文献类型：
--
作者：
Zoccal KF;Sorgi CA;Hori JI;Paula-Silva FW;Arantes EC;Serezani CH;Zamboni DS;Faccioli LH
全世界每年有数千人死于锯齿虎蜇伤。T.被细齿蛇毒化的受害者表现出局部或全身反应，最终导致肺水肿，可能导致死亡。然而，T. Serrulatus毒液（TsV）活性仍然未知。在这里，我们表明，TsV触发NLRP 3炎性小体激活通过K+流出。从机制上讲，TsV触发肺驻留细胞释放PGE 2，PGE 2通过E前列腺素受体2/4-cAMP-PKA-NFκ B依赖性机制诱导IL-1β产生。IL-1β/IL-1 R作用导致水肿和中性粒细胞聚集到肺部，导致TsV诱导的死亡。炎性小体激活通过IL-1β/IL-1 R信号传导触发LTB 4产生并进一步触发PGE 2。LTB 4-BLT 1/2通路的激活减少cAMP的产生，控制TsV诱导的炎症。外源性给药证实了LTB 4的抗炎活性，并消除了TsV诱导的死亡率。这些结果表明，LTB 4和PGE 2之间的平衡决定了IL-1β炎性体依赖性释放的量和毒液蛰入的结果。我们建议COX 1/2抑制作为一种有效的治疗干预蝎子毒液蛰入。 蝎子的毒液在世界范围内造成数千人死亡。在此，作者表明，毒液蛰入通过前列腺素E2起作用，导致炎性小体激活和肺部病理，由炎症限制性LTB 4抵消，并且考克斯抑制剂或外源性LTB 4挽救了小鼠中毒液诱导的死亡率。
Tityus serrulatus sting causes thousands of deaths annually worldwide. T. serrulatus-envenomed victims exhibit local or systemic reaction that culminates in pulmonary oedema, potentially leading to death. However, the molecular mechanisms underlying T. serrulatus venom (TsV) activity remain unknown. Here we show that TsV triggers NLRP3 inflammasome activation via K+ efflux. Mechanistically, TsV triggers lung-resident cells to release PGE2, which induces IL-1β production via E prostanoid receptor 2/4-cAMP-PKA-NFκB-dependent mechanisms. IL-1β/IL-1R actions account for oedema and neutrophil recruitment to the lungs, leading to TsV-induced mortality. Inflammasome activation triggers LTB4 production and further PGE2 via IL-1β/IL-1R signalling. Activation of LTB4-BLT1/2 pathway decreases cAMP generation, controlling TsV-induced inflammation. Exogenous administration confirms LTB4 anti-inflammatory activity and abrogates TsV-induced mortality. These results suggest that the balance between LTB4 and PGE2 determines the amount of IL-1β inflammasome-dependent release and the outcome of envenomation. We suggest COX1/2 inhibition as an effective therapeutic intervention for scorpion envenomation. Scorpion venom causes thousands of deaths worldwide. Here the authors show that the envenomation acts via prostaglandin E2 leading to inflammasome activation and lung pathology, counterbalanced by inflammation-limiting LTB4, and that COX inhibitors or exogenous LTB4 rescue the venom-induced mortality in mice.