A role for muscarinic receptors in neutrophil extracellular trap formation and levamisole-induced autoimmunity
A role for muscarinic receptors in neutrophil extracellular trap formation and levamisole-induced autoimmunity
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DOI：
10.1172/jci.insight.89780
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发表时间：
2017-02-09
期刊：
影响因子：
8
通讯作者：
Grayson, Peter C.
中科院分区：
文献类型：
--
作者：
Carmona-Rivera, Carmelo;Purmalek, Monica M.;Grayson, Peter C.
左旋咪唑是一种具有胆碱能特性的驱虫药，当为了盈利目的与可卡因一起使用时，已被认为与药物引起的脉管炎有关。中性粒细胞胞外陷阱(Net)的形成是一种以颗粒蛋白修饰的染色质排出为特征的细胞死亡机制。异常的网络形成和降解与特发性自身免疫性疾病有关，这些疾病与左旋咪唑诱导的自身免疫以及药物诱导的自身免疫具有相同的特征。这项研究的目的是确定左旋咪唑如何调节中性粒细胞生物学及其对血管系统的可能影响。暴露于左旋咪唑的小鼠和人中性粒细胞通过与M受体3型结合而增强网状形成。左旋咪唑诱导的NET中毒需要激活Akt和RAF/MEK/ERK通路，通过烟酰胺腺嘌呤二核苷酸磷酸氧化酶诱导ROS，以及激活肽基精氨酸脱亚胺酶。来自两组积极使用左旋咪唑掺杂可卡因的患者的血清显示出针对网络成分的自身抗体。从接触左旋咪唑的人身上获得的皮肤活检材料表明，中性粒细胞在血管炎症和血栓形成区域产生Net。左旋咪唑产生的Net对血管内皮细胞有毒性作用，并损害内皮依赖性血管松弛。胆碱能激动剂对中性粒细胞上M受体的刺激可能通过诱导炎症反应和中性粒细胞诱导的血管损伤而参与药物诱导的自身免疫的病理生理过程。
Levamisole, an anthelmintic drug with cholinergic properties, has been implicated in cases of drug-induced vasculitis when added to cocaine for profit purposes. Neutrophil extracellular trap (NET) formation is a cell death mechanism characterized by extrusion of chromatin decorated with granule proteins. Aberrant NET formation and degradation have been implicated in idiopathic autoimmune diseases that share features with levamisole-induced autoimmunity as well as in drug-induced autoimmunity. This study's objective was to determine how levamisole modulates neutrophil biology and its putative effects on the vasculature. Murine and human neutrophils exposed to levamisole demonstrated enhanced NET formation through engagement of muscarinic subtype 3 receptor. Levamisole-induced NETosis required activation of Akt and the RAF/MEK/ERK pathway, ROS induction through the nicotinamide adenine dinucleotide phosphate oxidase, and peptidylarginine deiminase activation. Sera from two cohorts of patients actively using levamisole-adulterated cocaine displayed autoantibodies against NET components. Cutaneous biopsy material obtained from individuals exposed to levamisole suggests that neutrophils produce NETs in areas of vasculitic inflammation and thrombosis. NETs generated by levamisole were toxic to endothelial cells and impaired endothelium-dependent vasorelaxation. Stimulation of muscarinic receptors on neutrophils by cholinergic agonists may contribute to the pathophysiology observed in drug-induced autoimmunity through the induction of inflammatory responses and neutrophil-induced vascular damage.