Brief Report: Drugs Implicated in Systemic Autoimmunity Modulate Neutrophil Extracellular Trap Formation.
Brief Report: Drugs Implicated in Systemic Autoimmunity Modulate Neutrophil Extracellular Trap Formation.
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DOI：
10.1002/art.40372
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发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Grayson PC
中科院分区：
文献类型：
--
作者：
Irizarry-Caro JA;Carmona-Rivera C;Schwartz DM;Khaznadar SS;Kaplan MJ;Grayson PC
异常的中性粒细胞胞外陷阱(Net)的形成被认为是高危个体诱导自身反应的一种机制。该研究的目的是评估与药物诱导的自身免疫有关的药物(肼和普鲁卡因胺)以及与药物诱导的自身免疫不太相关的药物(米诺环素和氯氮平)是否会导致净形成和/或防止净降解。人的中性粒细胞与感兴趣的药物孵育，并通过荧光显微镜对所产生的网络形成进行量化。评估了这些药物通过血清核酸酶干扰净降解的能力。用活性氧(ROS)、肽基精氨酸脱亚胺酶(PADS)和M受体的药理抑制剂，以及用流式细胞仪检测细胞内钙离子水平，研究药物诱导网络形成的途径。为了确定净蛋白载量是否随药物刺激和/或中性粒细胞来源的不同而不同，对特定药物诱导的净裂解产物进行了蛋白质组学分析，比较了来自健康捐赠者和自身免疫性疾病患者的中性粒细胞。肼和普鲁卡因胺显着诱导网状结构的形成，而米诺环素和氯氮平则不能。这些药物都不会显著损害净降解率。这些药物诱导的NETsis需要NADPH氧化酶和PAD4的激活。普鲁卡因胺通过与中性粒细胞上的M受体结合来触发NETs，而肼丙嗪则调节细胞内钙的释放。在肼和普鲁卡因胺诱导的NETs中，观察到蛋白质含量的差异，尤其是组蛋白含量。通常与药物诱导的自身免疫有关的药物通过共同和特定的途径触发网络形成，显示不同的蛋白质货物。内毒素血症可能在药物诱导自身免疫的发病机制中起一定作用。
Aberrant neutrophil extracellular trap (NET) formation has been implicated as a mechanism to induce auto-reactivity in at-risk individuals. The study objective was to assess whether medications implicated in cases of drug-induced autoimmunity (hydralazine and procainamide) and medications less commonly associated with drug-induced autoimmunity (minocycline and clozapine) induce NET formation and/or prevent NET degradation. Human neutrophils were incubated with the drugs of interest and resultant NET formation was quantified by fluorescent microscopy. The ability of these drugs to interfere with NET degradation by serum nucleases was assessed. Pathways of drug-induced NET formation were studied with pharmacologic inhibitors of reactive oxygen species (ROS), peptidylarginine deiminases (PADs), and muscarinic receptors, and by assessment of intracellular calcium levels by flow cytometry. To determine if NET protein cargo varies by drug stimuli and/or neutrophil source, proteomic analysis of NET lysates induced by specific medications was compared using neutrophils from healthy donors and from patients with autoimmune diseases. Hydralazine and procainamide significantly induced NET formation while minocycline and clozapine did not. None of the medications significantly impaired NET degradation. NETosis induced by these drugs required NADPH oxidase and PAD4 activation. Procainamide triggered NETs via muscarinic receptor engagement on neutrophils, while hydralazine modulated calcium release from intracellular stores. Differences in protein cargo, particularly histone content, were observed in NETs induced by hydralazine and procainamide. Medications commonly implicated in drug-induced autoimmunity trigger NET formation displaying distinct protein cargo, via common and specific pathways. NETosis may play a role in the pathogenesis of drug-induced autoimmunity.
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影响因子：
8
作者：
Carmona-Rivera, Carmelo;Purmalek, Monica M.;Grayson, Peter C.
通讯作者：
Grayson, Peter C.
影响因子：
17.1
作者：
Khandpur R;Carmona-Rivera C;Vivekanandan-Giri A;Gizinski A;Yalavarthi S;Knight JS;Friday S;Li S;Patel RM;Subramanian V;Thompson P;Chen P;Fox DA;Pennathur S;Kaplan MJ
通讯作者：
Kaplan MJ
DOI：
10.4049/jimmunol.0902199
发表时间：
2010-03-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Denny MF;Yalavarthi S;Zhao W;Thacker SG;Anderson M;Sandy AR;McCune WJ;Kaplan MJ
通讯作者：
Kaplan MJ
影响因子：
56.9
作者：
Brinkmann, V;Reichard, U;Zychlinsky, A
通讯作者：
Zychlinsky, A
DOI：
10.1196/annals.1422.019
发表时间：
2007-01-01
期刊：
AUTOIMMUNITY, PT D
影响因子：
--
作者：
Borchers, Andrea T.;Keen, Carl L.;Gershwin, M. Eric
通讯作者：
Gershwin, M. Eric