Microsomal prostaglandin E synthase-1 gene deletion impairs neuro-immune circuitry of the cholinergic anti-inflammatory pathway in endotoxaemic mouse spleen.
Microsomal prostaglandin E synthase-1 gene deletion impairs neuro-immune circuitry of the cholinergic anti-inflammatory pathway in endotoxaemic mouse spleen.
复制标题
DOI：
10.1371/journal.pone.0193210
复制
发表时间：
2018
期刊：
影响因子：
3.7
通讯作者：
Lampa J
中科院分区：
文献类型：
--
作者：
Revathikumar P;Estelius J;Karmakar U;Le Maître E;Korotkova M;Jakobsson PJ;Lampa J
胆碱能抗炎通路（CAP）是一种先天性神经反射，其中副交感神经和交感神经共同作用以控制炎症。通过迷走神经刺激（VNS）激活CAP为治疗炎症性疾病的新治疗策略铺平了道路。最近，我们发现，VNS介导的脾乙酰胆碱（ACh）的释放和随后的免疫抑制反应LPS相关的炎症是受损的小鼠缺乏微粒体前列腺素E合成酶-1（mPGES-1）的表达，负责前列腺素E2合成的关键酶。在这里，我们进一步研究了mPGES-1缺乏对脾脏中各种分子/细胞事件的后果，这对于内毒素血症小鼠中VNS的最佳功能至关重要。首先，在mPGES-1（+/+）和（-/-）小鼠中，VNS诱导脾去甲肾上腺素（NE）释放。与mPGES-1（+/+）相比，NE对mPGES-1（-/-）脾细胞中细胞因子的免疫调节作用受到强烈损害。有趣的是，虽然LPS增加了mPGES-1（+/+）脾细胞中胆碱乙酰转移酶（ChAT）蛋白水平，但它未能在mPGES-1（-/-）脾细胞中发挥类似的作用，尽管β2 AR蛋白表达未改变。此外，尼古丁在体外抑制LPS激活的mPGES-1（+/+）脾细胞释放TNFα。然而，尼古丁的这种免疫抑制作用在mPGES-1（-/-）小鼠脾细胞和用mPGES-1抑制剂处理的人PBMC中均被逆转。总之，我们的数据牵连PGE 2作为一个重要的调解人乙酰胆碱合成和去甲肾上腺素/胆碱能分子事件在脾脏，构成了CAP免疫调节的重要组成部分。我们的研究结果表明，CAP的胆碱能和PG系统之间可能存在联系，这对VNS的治疗可能具有临床意义。
The cholinergic anti-inflammatory pathway (CAP) is an innate neural reflex where parasympathetic and sympathetic nerves work jointly to control inflammation. Activation of CAP by vagus nerve stimulation (VNS) has paved way for novel therapeutic strategies in treating inflammatory diseases. Recently, we discovered that VNS mediated splenic acetylcholine (ACh) release and subsequent immunosuppression in response to LPS associated inflammation is impaired in mice lacking microsomal prostaglandin E synthase-1 (mPGES-1) expression, a key enzyme responsible for prostaglandin E2 synthesis. Here, we have further investigated the consequences of mPGES-1 deficiency on various molecular/cellular events in the spleen which is critical for the optimal functioning of VNS in endotoxaemic mice. First, VNS induced splenic norepinephrine (NE) release in both mPGES-1 (+/+) and (-/-) mice. Compared to mPGES-1 (+/+), immunomodulatory effects of NE on cytokines were strongly compromised in mPGES-1 (-/-) splenocytes. Interestingly, while LPS increased choline acetyltransferase (ChAT) protein level in mPGES-1 (+/+) splenocytes, it failed to exert similar effects in mPGES-1 (-/-) splenocytes despite unaltered β2 AR protein expression. In addition, nicotine inhibited TNFα release by LPS activated mPGES-1 (+/+) splenocytes in vitro. However, such immunosuppressive effects of nicotine were reversed both in mPGES-1 (-/-) mouse splenocytes and human PBMC treated with mPGES-1 inhibitor. In summary, our data implicate PGE2 as an important mediator of ACh synthesis and noradrenergic/cholinergic molecular events in the spleen that constitute a crucial part of the CAP immune regulation. Our results suggest a possible link between cholinergic and PG system of CAP that may be of clinical significance in VNS treatment.
登录
查看更多内容
影响因子：
5.3
作者：
Grailer JJ;Haggadone MD;Sarma JV;Zetoune FS;Ward PA
通讯作者：
Ward PA
影响因子：
3.5
作者：
Bonaz, B.;Sinniger, V.;Pellissier, S.
通讯作者：
Pellissier, S.
影响因子：
8.3
作者：
Dawson J;Pierce D;Dixit A;Kimberley TJ;Robertson M;Tarver B;Hilmi O;McLean J;Forbes K;Kilgard MP;Rennaker RL;Cramer SC;Walters M;Engineer N
通讯作者：
Engineer N
影响因子：
5.7
作者：
Olofsson, Peder S.;Katz, David A.;Chavan, Sangeeta S.
通讯作者：
Chavan, Sangeeta S.
DOI：
10.4049/jimmunol.1101029
发表时间：
2012-01-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Kalinski P
通讯作者：
Kalinski P