NLRP1 and NLRP3 inflammasomes are essential for distinct outcomes of decreased cytokines but enhanced bacterial killing upon chronic Nod2 stimulation
NLRP1 and NLRP3 inflammasomes are essential for distinct outcomes of decreased cytokines but enhanced bacterial killing upon chronic Nod2 stimulation
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DOI：
10.1152/ajpgi.00297.2012
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发表时间：
2013-03-01
影响因子：
4.5
通讯作者：
Abraham, Clara
中科院分区：
文献类型：
--
作者：
Hedl, Matija;Abraham, Clara
在慢性微生物暴露和模式识别受体（PRR）刺激后，骨髓衍生细胞相对于急性PRR刺激经历不同的转录程序，其中促炎途径被下调。然而，其他宿主反应途径可能受到差异调节，这一概念相对未被探索。了解调节慢性微生物暴露结果的机制对于持续感染或粘膜表面（如肠道）的情况非常重要。细胞内PRR核苷酸寡聚化结构域2（Nod 2）赋予发展克罗恩病（CD）的最高遗传风险。我们以前确定了慢性Nod 2刺激后介导促炎通路下调的机制;在这里，我们试图定义慢性Nod 2刺激如何调节细菌杀伤。我们发现，尽管通过PRR和活细菌再刺激后下调细胞因子分泌，但人类单核细胞衍生的巨噬细胞的慢性Nod 2刺激增强了细菌杀伤;这种双重调节在CD Nod 2风险携带者中不存在。我们表明，慢性Nod 2介导的重编程的人单核细胞衍生的巨噬细胞的增强的细菌杀伤的状态需要上调活性氧/氮物质途径的功能，通过增加p67 phox/p47 phox/一氧化氮合酶-2的表达;选择性地敲低这些基因逆转增强的细菌杀伤。重要的是，我们发现，在慢性Nod 2刺激期间，NLRP 3/NLRP 1炎性体介导的caspase-1活化与随后的IL-1分泌对于随后的分叉至下调的促炎细胞因子和上调的细菌杀伤是必不可少的。因此，我们确定了慢性刺激CD相关蛋白Nod 2后介导不同炎症和杀微生物结果的机制。
Upon chronic microbial exposure and pattern-recognition receptor (PRR) stimulation, myeloid-derived cells undergo a distinct transcriptional program relative to acute PRR stimulation, with proinflammatory pathways being downregulated. However, other host-response pathways might be differentially regulated, and this concept has been relatively unexplored. Understanding mechanisms regulating chronic microbial exposure outcomes is important for conditions of ongoing infection or at mucosal surfaces, such as the intestine. The intracellular PRR nucleotide oligomerization domain 2 (Nod2) confers the highest genetic risk toward developing Crohn's disease (CD). We previously identified mechanisms mediating downregulation of proinflammatory pathways upon chronic Nod2 stimulation; here we sought to define how chronic Nod2 stimulation regulates bacterial killing. We find that, despite downregulating cytokine secretion upon restimulation through PRR and live bacteria, chronic Nod2 stimulation of human monocyte-derived macrophages enhances bacterial killing; this dual regulation is absent in CD Nod2-risk carriers. We show that chronic Nod2-mediated reprogramming of human monocyte-derived macrophages to a state of enhanced bacterial killing requires upregulated reactive oxygen/nitrogen species pathway function through increased p67phox/p47phox/nitric oxide synthase-2 expression; selectively knocking down each of these genes reverses the enhanced bacterial killing. Importantly, we find that, during chronic Nod2 stimulation, NLRP3/NLRP1 inflammasome-mediated caspase-1 activation with subsequent IL-1 secretion is essential for the subsequent bifurcation to downregulated proinflammatory cytokines and upregulated bacterial killing. Therefore, we identify mechanisms mediating the distinct inflammatory and microbicidal outcomes upon chronic stimulation of the CD-associated protein Nod2.