Non-canonical NLRP3 inflammasome activation and IL-1β signaling are necessary to L. amazonensis control mediated by P2X7 receptor and leukotriene B4
Non-canonical NLRP3 inflammasome activation and IL-1β signaling are necessary to L. amazonensis control mediated by P2X7 receptor and leukotriene B4
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DOI：
10.1371/journal.ppat.1007887
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发表时间：
2019-06-01
期刊：
影响因子：
6.7
通讯作者：
Coutinho-Silva, Robson
中科院分区：
文献类型：
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作者：
Chaves, Mariana M.;Sinflorio, Debora A.;Coutinho-Silva, Robson
利什曼病是一种被忽视的热带疾病，影响着全世界数百万人。P2 X7受体与亚马逊利什曼原虫的消除有关。由P2 X7受体激活引起的生物学应答已经被充分记录，包括细胞凋亡、吞噬作用、细胞因子释放，例如IL-1 β。结果表明，NLRP 3炎性体激活和IL-1 β信号通路参与了抗L.亚马逊河。此外，我们的小组已经表明，L。通过P2 X7受体激活的亚马逊消除依赖于白三烯B-4（LTB 4）的产生和释放。因此，我们调查了L.通过P2 X7受体和LTB 4的亚马孙消除涉及NLRP 3炎性体激活和IL-1 β信号传导。我们发现，来自用ATP或LTB 4处理的NLRP 3（-/-）、ASC（-/-）、Casp-1/11（-/-）、gp 91（phox-/-）和IL-1 R（-/-）小鼠的巨噬细胞没有像在WT小鼠中观察到的那样降低寄生虫负荷。当用外源性IL-1 β处理ASC（-/-）巨噬细胞时，注意到寄生虫杀死，然而，我们没有看到IL-1 R（-/-）巨噬细胞中的寄生虫负荷减少。类似地，来自用IL-1 β处理的P2 X7受体缺陷小鼠的巨噬细胞也显示出降低的寄生虫负荷。此外，当我们感染Casp-11（-/-）巨噬细胞时，ATP和LTB 4都不能降低寄生虫负荷，Casp-11（-/-）小鼠对L.感染亚马逊河病毒的小鼠比野生型小鼠更少。P2X7（-/-）L.用外源性LTB 4局部处理的亚马逊河原虫感染的小鼠显示出对感染的抗性，其特征在于与未处理的P2 X7（-/-）小鼠相比寄生虫负荷较低和病变较小。当用IL-1 β处理感染的P2 X7（-/-）小鼠时，也观察到类似的观察结果，即，与P2 X7（-/-）小鼠相比，寄生虫负荷更低，病变更小。这些数据表明L. P2 X7受体和LTB 4介导的亚马逊利什曼原虫消除依赖于非典型的NLRP 3炎性小体激活、ROS产生和IL-1 β信号传导。是一种原生动物寄生虫，感染人类并引起多种疾病。亚马逊利什曼原虫引起皮肤利什曼病（CL）和粘膜皮肤利什曼病（MCL）。利什曼原虫优先感染巨噬细胞。在巨噬细胞中，有几种机制被描述为控制L。亚马逊河感染在此，我们发现P2 X7受体和LTB 4可以清除L.通过依赖于非经典NLRP 3炎性体激活和IL-1 β信号传导的途径，在巨噬细胞中表达亚马逊河病毒。
Leishmaniasis is a neglected tropical disease affecting millions of individuals worldwide. P2X7 receptor has been linked to the elimination of Leishmania amazonensis. Biological responses evoked by P2X7 receptor activation have been well-documented, including apoptosis, phagocytosis, cytokine release, such as IL-1 beta. It was demonstrated that NLRP3 inflammasome activation and IL-1 beta signaling participated in resistance against L. amazonensis. Furthermore, our group has shown that L. amazonensis elimination through P2X7 receptor activation depended on leukotriene B-4 (LTB4) production and release. Therefore, we investigated whether L. amazonensis elimination by P2X7 receptor and LTB4 involved NLRP3 inflammasome activation and IL-1 beta signaling. We showed that macrophages from NLRP3(-/-), ASC(-/-), Casp-1/11(-/-), gp91(phox-/- ,) and IL-1R(-/-) mice treated with ATP or LTB4 did not decrease parasitic load as was observed in WT mice. When ASC(-/-) macrophages were treated with exogenous IL-1 beta, parasite killing was noted, however, we did not see parasitic load reduction in IL-1R(-/-) macrophages. Similarly, macrophages from P2X7 receptor-deficient mice treated with IL-1 beta also showed decreased parasitic load. In addition, when we infected Casp-11(-/-) macrophages, neither ATP nor LTB4 were able to reduce parasitic load, and Casp-11(-/-) mice were more susceptible to L. amazonensis infection than were WT mice. Furthermore, P2X7(-/-) L. amazonensis-infected mice locally treated with exogenous LTB4 showed resistance to infection, characterized by lower parasite load and smaller lesions compared to untreated P2X7(-/-) mice. A similar observation was noted when infected P2X7(-/-) mice were treated with IL-1 beta, i.e., lower parasite load and smaller lesions compared to P2X7(-/-) mice. These data suggested that L. amazonensis elimination mediated by P2X7 receptor and LTB4 was dependent on non-canonical NLRP3 inflammasome activation, ROS production, and IL-1 beta signaling.Author summary Leishmania spp. is a protozoan parasite that infects human and causes several diseases. Leishmania amazonensis causes cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (MCL). Leishmania parasites preferentially infect macrophages. In macrophages, several mechanisms have been described as controlling L. amazonensis infection. Here, we showed that P2X7 receptor and LTB4 eliminated L. amazonensis in macrophages by a pathway dependent on non-canonical NLRP3 inflammasome activation and IL-1 beta signaling.