Mast cell chymase reduces the toxicity of Gila monster venom, scorpion venom, and vasoactive intestinal polypeptide in mice
Mast cell chymase reduces the toxicity of Gila monster venom, scorpion venom, and vasoactive intestinal polypeptide in mice
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DOI：
10.1172/jci46139
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发表时间：
2011-10-01
影响因子：
15.9
通讯作者：
Galli, Stephen J.
中科院分区：
文献类型：
--
作者：
Akahoshi, Mitsuteru;Song, Chang Ho;Galli, Stephen J.
肥大细胞脱颗粒在过敏反应和过敏性疾病的发病机制中很重要。许多动物毒液含有可诱导肥大细胞脱颗粒的成分，这被认为是导致毒液引起的病理和死亡的原因。然而，我们最近报道的证据表明，肥大细胞可以增强小鼠对某些蛇毒液的抵抗力，并且小鼠肥大细胞衍生的羧肽酶 A3 (CPA3) 可以促进这种效果。在这里，我们研究了肥大细胞是否可以增强对希拉毒蜥毒液（该毒液的有毒成分（毒蛇皮素））以及结构相似的哺乳动物肽——血管活性肠多肽（VIP）的抵抗力。使用两种类型的肥大细胞缺陷小鼠，以及选择性缺乏CPA3活性或食糜酶小鼠肥大细胞蛋白酶-4（MCPT4）的小鼠，我们发现肥大细胞和可降解毒蜥皮素的MCPT4可以增强宿主对吉拉毒蜥毒液毒性的抵抗力。肥大细胞和 MCPT4 还可以限制与高浓度 VIP 相关的毒性，并可以降低由 2 种蝎子毒液引起的发病率和死亡率。我们的研究结果支持这样的观点，即肥大细胞可以通过降解多种动物毒素来增强先天防御，并且除了 CPA3 之外，MCPT4 的释放也可以促进肥大细胞的功能。
Mast cell degranulation is important in the pathogenesis of anaphylaxis and allergic disorders. Many animal venoms contain components that can induce mast cell degranulation, and this has been thought to contribute to the pathology and mortality caused by envenomation. However, we recently reported evidence that mast cells can enhance the resistance of mice to the venoms of certain snakes and that mouse mast cell-derived carboxypeptidase A3 (CPA3) can contribute to this effect. Here, we investigated whether mast cells can enhance resistance to the venom of the Gila monster, a toxic component of that venom (helodermin), and the structurally similar mammalian peptide, vasoactive intestinal polypeptide (VIP). Using 2 types of mast cell-deficient mice, as well as mice selectively lacking CPA3 activity or the chymase mouse mast cell protease-4 (MCPT4), we found that mast cells and MCPT4, which can degrade helodermin, can enhance host resistance to the toxicity of Gila monster venom. Mast cells and MCPT4 also can limit the toxicity associated with high concentrations of VIP and can reduce the morbidity and mortality induced by venoms from 2 species of scorpions. Our findings support the notion that mast cells can enhance innate defense by degradation of diverse animal toxins and that release of MCPT4, in addition to CPA3, can contribute to this mast cell function.