NLRP3 inflammasome contributes to inflammation after intracerebral hemorrhage.
NLRP3 inflammasome contributes to inflammation after intracerebral hemorrhage.
复制标题
DOI：
10.1002/ana.24070
复制
发表时间：
2014-02
影响因子：
11.2
通讯作者：
Tang, Jiping
中科院分区：
文献类型：
--
作者：
Ma, Qingyi;Chen, Sheng;Hu, Qin;Feng, Hua;Zhang, John H.;Tang, Jiping
NLRP 3（NALP 3，cryopyrin）炎性小体是先天免疫系统的关键组分，可促进caspase-1和白细胞介素（IL）-1β加工，从而放大炎症反应。在这里，我们研究了NLRP 3敲低是否减少中性粒细胞浸润，减少脑水肿，并改善脑出血（ICH）小鼠模型的神经功能。我们还确定了由线粒体通透性转换孔（mPTP）控制的线粒体活性氧（ROS）是否会在ICH后触发NLRP 3炎性小体激活。通过向小鼠脑内注射自体动脉血（30μl）诱导ICH。在ICH前24小时给予NLRP 3小干扰RNA。将mPTP抑制剂（TRO-19622）或特异性线粒体ROS清除剂（Mito-TEMPO）与血液共注射。在幼稚动物中，应用鱼藤酮（一种呼吸链复合物I抑制剂）诱导线粒体ROS产生，然后进行TRO-19622或Mito-TEMPO处理。评估了神经功能缺陷、脑水肿、酶联免疫吸附测定、蛋白质印迹、体内化学交联、活性氧测定和免疫荧光。ICH激活NLRP 3炎性体。NLRP 3敲低减少脑水肿，并在24小时降低髓过氧化物酶（MPO）水平，并改善ICH后24至72小时的神经功能。TRO-19622或Mito-TEMPO降低了ICH后的ROS、NLRP 3炎性体组分和MPO水平。在幼稚动物中，鱼藤酮给药诱导mPTP形成、ROS产生和NLRP 3炎性小体活化，然后通过TRO-19622或Mito-TEMPO减少。NLRP 3炎性小体通过释放IL-1β和促进中性粒细胞浸润来放大ICH后的炎症反应。线粒体ROS可能是NLRP 3炎性小体激活的主要触发因素。我们的研究结果表明，抑制NLRP 3炎性体可以有效地减少ICH后的炎症反应。
The NLRP3 (NALP3, cryopyrin) inflammasome, a key component of the innate immune system, facilitates caspase-1 and interleukin (IL)–1β processing, which amplifies the inflammatory response. Here, we investigated whether NLRP3 knockdown decreases neutrophil infiltration, reduces brain edema, and improves neurological function in an intracerebral hemorrhage (ICH) mouse model. We also determined whether mitochondrial reactive oxygen species (ROS) governed by mitochondrial permeability transition pores (mPTPs) would trigger NLRP3 inflammasome activation following ICH. ICH was induced by injecting autologous arterial blood (30μl) into a mouse brain. NLRP3 small interfering RNAs were administered 24 hours before ICH. A mPTP inhibitor (TRO-19622) or a specific mitochondria ROS scavenger (Mito-TEMPO) was coinjected with the blood. In naive animals, rotenone, which is a respiration chain complex I inhibitor, was applied to induce mitochondrial ROS production, and followed by TRO-19622 or Mito-TEMPO treatment. Neurological deficits, brain edema, enzyme-linked immunosorbent assay, Western blot, in vivo chemical cross-linking, ROS assay, and immunofluorescence were evaluated. ICH activated the NLRP3 inflammasome. NLRP3 knockdown reduced brain edema and decreased myeloper-oxidase (MPO) levels at 24 hours, and improved neurological functions from 24 to 72 hours following ICH. TRO-19622 or Mito-TEMPO reduced ROS, NLRP3 inflammasome components, and MPO levels following ICH. In naive animals, rotenone administration induced mPTP formation, ROS generation, and NLRP3 inflammasome activation, which were then reduced by TRO-19622 or Mito-TEMPO. The NLRP3 inflammasome amplified the inflammatory response by releasing IL-1β and promoting neutrophil infiltration following ICH. Mitochondria ROS may be a major trigger of NLRP3 inflammasome activation. The results of our study suggest that the inhibition of the NLRP3 inflammasome may effectively reduce the inflammatory response following ICH.
登录
查看更多内容
DOI：
10.1042/bj20081386
发表时间：
2009-01-01
期刊：
The Biochemical journal
影响因子：
--
作者：
Murphy MP
通讯作者：
Murphy MP
影响因子：
4.8
作者：
Li, NY;Ragheb, K;Robinson, JP
通讯作者：
Robinson, JP
影响因子：
8.3
作者：
GARCIA, JH;WAGNER, S;HU, XJ
通讯作者：
HU, XJ
影响因子：
14.8
作者：
Rynkowski, Michal A.;Kim, Grace H.;Connolly, E. Sander
通讯作者：
Connolly, E. Sander
影响因子：
4.1
作者：
Masada, T;Hua, Y;Keep, RF
通讯作者：
Keep, RF