Macrophage priming is dispensable for NLRP3 inflammasome activation and restriction of Leishmania amazonensis replication
Macrophage priming is dispensable for NLRP3 inflammasome activation and restriction of Leishmania amazonensis replication
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DOI：
10.1002/jlb.ma1118-471r
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发表时间：
2019-09-01
影响因子：
5.5
通讯作者：
Zannboni, Dario S.
中科院分区：
文献类型：
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作者：
de Carvalho, Rena N. V. H.;Silva, Alexandre L. N.;Zannboni, Dario S.
NLRP 3炎性体响应于多种刺激而被激活，并触发半胱天冬酶-1（CASP 1）的激活、IL-1 β的产生和炎症。NLRP 3的激活需要两个信号。第一个导致与炎症相关的特定基因的转录调节，第二个是当病原体，毒素或特定化合物破坏细胞膜和/或触发活性氧（ROS）的产生时触发的。在这里，我们评估的第一个信号（引发）的NLRP 3炎性小体在骨髓源性巨噬细胞（BMDM）感染亚马逊利什曼原虫激活的要求。我们发现，BMDM表达足够水平的炎性体组分NLRP 3、ASC和CASP 1，以使NLRP 3炎性体能够响应感染而组装和活化。因此，ASC斑点的形成、CASP 1活化（通过荧光染料FAM-YVAD测量）和L.亚马逊复制通过NLRP 3炎性体。相比之下，BMDM引发是CASP 1切割（p20）和IL-1 β分泌所需的，因为引发引发了pro-IL-1 β和CASP 11的强烈上调，这对CASP 1和IL-1 β的有效加工很重要。总之，我们的数据揭示了利什曼原虫激活巨噬细胞中NLRP 3的细胞和分子过程，这一过程对利什曼病的结局很重要。
The NLRP3 inflammasome is activated in response to multiple stimuli and triggers activation of caspase-1 (CASP1), IL-1 beta production, and inflammation. NLRP3 activation requires two signals. The first leads to transcriptional regulation of specific genes related to inflammation, and the second is triggered when pathogens, toxins, or specific compounds damage cellular membranes and/or trigger the production of reactive oxygen species (ROS). Here, we assess the requirement of the first signal (priming) for the activation of the NLRP3 inflammasome in bone marrow-derived macrophages (BMDMs) infected with Leishmania amazonensis. We found that BMDMs express the inflammasome components NLRP3, ASC, and CASP1 at sufficient levels to enable the assembly and activation of NLRP3 inflammasome in response to infection. Therefore, priming was not required for the formation of ASC specks, CASP1 activation (measured by fluorescent dye FAM-YVAD), and restriction of L. amazonensis replication via the NLRP3 inflammasome. By contrast, BMDM priming was required for CASP1 cleavage (p20) and IL-1 beta secretion, because priming triggers robust up-regulation of pro-IL-1 beta and CASP11 that are important for efficient processing of CASP1 and IL-1 beta. Taken together, our data shed light into the cellular and molecular processes involved in activation of the NLRP3 in macrophages by Leishmania, a process that is important for the outcome of Leishmaniasis.