A Novel Pathway for Inducible Nitric-oxide Synthase Activation through Inflammasomes
A Novel Pathway for Inducible Nitric-oxide Synthase Activation through Inflammasomes
复制标题
DOI：
10.1074/jbc.m110.124297
复制
发表时间：
2010-10-15
影响因子：
4.8
通讯作者：
Bortoluci, Karina R.
中科院分区：
文献类型：
--
作者：
Buzzo, Carina L.;Campopiano, Julia C.;Bortoluci, Karina R.
鞭毛蛋白的先天免疫识别由跨膜TLR5和细胞质Nlrc4 (nod样受体家族CARD （caspase激活募集域）结构域4)/Naip5（神经元凋亡抑制蛋白5）共享。TLR5通过MYD88途径激活炎症基因，而Nlrc4和Naip5组装称为炎症小体的多蛋白复合物，最终导致caspase-1激活，IL-1 β /IL-18分泌和焦亡。虽然TLR5和Naip5/Nlrc4通路都协同清除感染，但对它们各自的相关抗病原体效应机制知之甚少。在这里，我们发现细胞质鞭毛蛋白（FLA-BSDot）能够激活iNOS，这是一种先前与TLR5途径相关的酶。在Nlrc4-或naip5缺失的巨噬细胞中，我们发现这两种受体都参与了FLA-BSDot对iNOS的激活。此外，与细胞外鞭毛蛋白（FLA-BS）不同，在缺乏caspase-1的情况下，细胞内鞭毛蛋白对iNOS的激活完全被消除。有趣的是，IL-1 β和IL-18似乎对fla - bsdot介导的iNOS产生并不重要。总之，我们的数据定义了一种额外的抗病原体效应机制，通过Naip5和Nlrc4炎症小体运作，并阐明了一种激活iNOS的新型信号转导途径。
Innate immune recognition of flagellin is shared by transmembrane TLR5 and cytosolic Nlrc4 (NOD-like receptor family CARD (caspase activation recruitment domain) domain containing 4)/Naip5 (neuronal apoptosis inhibitory protein 5). TLR5 activates inflammatory genes through MYD88 pathway, whereas Nlrc4 and Naip5 assemble multiprotein complexes called inflammasomes, culminating in caspase-1 activation, IL-1 beta/IL-18 secretion, and pyroptosis. Although both TLR5 and Naip5/Nlrc4 pathways cooperate to clear infections, little is known about the relative anti-pathogen effector mechanisms operating through each of them. Here we show that the cytosolic flagellin (FLA-BSDot) was able to activate iNOS, an enzyme previously associated with TLR5 pathway. Using Nlrc4- or Naip5-deficient macrophages, we found that both receptors are involved in iNOS activation by FLA-BSDot. Moreover, distinct from extracellular flagellin (FLA-BS), iNOS activation by intracellular flagellin is completely abrogated in the absence of caspase-1. Interestingly, IL-1 beta and IL-18 do not seem to be important for FLA-BSDot-mediated iNOS production. Together, our data defined an additional anti-pathogen effector mechanism operated through Naip5 and Nlrc4 inflammasomes and illustrated a novel signaling transduction pathway that activates iNOS.