有机磷二异丙基氟磷酸盐急性中毒后大鼠大脑先天免疫细胞炎症表型的时空变化

IF 9.3 1区 医学 Q1 IMMUNOLOGY
Peter M Andrew, Jeremy A MacMahon, Pedro N Bernardino, Yi-Hua Tsai, Brad A Hobson, Valerie A Porter, Sydney L Huddleston, Audrey S Luo, Donald A Bruun, Naomi H Saito, Danielle J Harvey, Amy Brooks-Kayal, Abhijit J Chaudhari, Pamela J Lein
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引用次数: 0

摘要

胆碱酯酶抑制性有机磷(OP)急性中毒可产生危及生命的胆碱能危象和癫痫状态(SE)。幸存者通常会出现长期的神经系统后遗症,包括自发性复发性癫痫发作(SRS)和认知能力受损。大量研究表明,OP 诱导的神经炎症是导致这些慢性后遗症的致病机制之一;然而,人们对急性 OP 中毒后大脑中先天性免疫细胞的炎症表型知之甚少。因此,本研究旨在描述急性 OP(二异丙基氟磷酸酯)中毒后小胶质细胞和星形胶质细胞炎症表型的自然史。给成年雌雄Sprague-Dawley大鼠注射单剂量DFP(4毫克/千克,皮下注射),然后采取标准医疗对策。通过使用改良的拉辛量表监测癫痫发作,动物在几分钟内就出现了苯二氮卓抗性 SE。在暴露后 1、3、7、14 和 28 d(DPE),我们使用转运体蛋白(TSPO)正电子发射断层扫描(PET)和磁共振成像(MRI)对神经炎症进行了评估。在所有检查的脑区和时间点,我们都观察到雌雄动物的放射性示踪剂摄取量持续升高。另外一组动物在相同的时间点被安乐死,以收集组织进行免疫组化分析。小胶质细胞标记物 IBA-1 与 iNOS 或 Arg1 的共定位分别用于识别促炎和抗炎小胶质细胞;星形胶质细胞标记物 GFAP 与 C3 或 S100A10 的共定位分别用于识别促炎和抗炎星形胶质细胞。在中毒后的第一个月,我们观察到小胶质细胞和星形胶质细胞群的炎症特征发生了变化,主要表现在梨状皮层和杏仁核区域的高强度炎症病变。在这些区域,iNOS+促炎性小胶质细胞密度在3和7 DPE达到峰值,而抗炎性Arg1+小胶质细胞密度在14 DPE达到峰值。促炎性和抗炎性星形胶质细胞在 7 DPE 内出现,C3+ 促炎性和 S100A10+ 抗炎性星形胶质细胞的比例大致相同,并持续到 28 DPE。总之,OP 中毒后,小胶质细胞和星形胶质细胞采用了混合炎症表型,这种表型在暴露后一个月内不断演变。这些活化的细胞群在梨状体和杏仁核区域最为突出,男性多于女性。小胶质细胞和星形胶质细胞反应之间的时间关系表明,最初的小胶质细胞活动可能会影响延迟的、持续的星形胶质细胞反应。此外,我们的研究结果还确定了抑制 OP 诱导的两性神经炎症反应的潜在窗口,以评估抗炎在这方面的治疗效果。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Shifts in the spatiotemporal profile of inflammatory phenotypes of innate immune cells in the rat brain following acute intoxication with the organophosphate diisopropylfluorophosphate.

Acute intoxication with cholinesterase inhibiting organophosphates (OP) can produce life-threatening cholinergic crisis and status epilepticus (SE). Survivors often develop long-term neurological consequences, including spontaneous recurrent seizures (SRS) and impaired cognition. Numerous studies implicate OP-induced neuroinflammation as a pathogenic mechanism contributing to these chronic sequelae; however, little is known about the inflammatory phenotype of innate immune cells in the brain following acute OP intoxication. Thus, the aim of this study was to characterize the natural history of microglial and astrocytic inflammatory phenotypes following acute intoxication with the OP, diisopropylfluorophosphate (DFP). Adult male and female Sprague-Dawley rats were administered a single dose of DFP (4 mg/kg, sc) followed by standard medical countermeasures. Within minutes, animals developed benzodiazepine-resistant SE as determined by monitoring seizures using a modified Racine scale. At 1, 3, 7, 14, and 28 d post-exposure (DPE), neuroinflammation was assessed using translocator protein (TSPO) positron emission tomography (PET) and magnetic resonance imaging (MRI). In both sexes, we observed consistently elevated radiotracer uptake across all examined brain regions and time points. A separate group of animals was euthanized at these same time points to collect tissues for immunohistochemical analyses. Colocalization of IBA-1, a marker for microglia, with iNOS or Arg1 was used to identify pro- and anti-inflammatory microglia, respectively; colocalization of GFAP, a marker for astrocytes, with C3 or S100A10, pro- and anti-inflammatory astrocytes, respectively. We observed shifts in the inflammatory profiles of microglia and astrocyte populations during the first month post-intoxication, largely in hyperintense inflammatory lesions in the piriform cortex and amygdala regions. In these areas, iNOS+ proinflammatory microglial cell density peaked at 3 and 7 DPE, while anti-inflammatory Arg1+ microglia cell density peaked at 14 DPE. Pro- and anti-inflammatory astrocytes emerged within 7 DPE, and roughly equal ratios of C3+ pro-inflammatory and S100A10+ anti-inflammatory astrocytes persisted at 28 DPE. In summary, microglia and astrocytes adopted mixed inflammatory phenotypes post-OP intoxication, which evolved over one month post exposure. These activated cell populations were most prominent in the piriform and amygdala areas and were more abundant in males compared to females. The temporal relationship between microglial and astrocytic responses suggests that initial microglial activity may influence delayed, persistent astrocytic responses. Further, our findings identify putative windows for inhibition of OP-induced neuroinflammatory responses in both sexes to evaluate the therapeutic benefit of anti-inflammation in this context.

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来源期刊
Journal of Neuroinflammation
Journal of Neuroinflammation 医学-神经科学
CiteScore
15.90
自引率
3.20%
发文量
276
审稿时长
1 months
期刊介绍: The Journal of Neuroinflammation is a peer-reviewed, open access publication that emphasizes the interaction between the immune system, particularly the innate immune system, and the nervous system. It covers various aspects, including the involvement of CNS immune mediators like microglia and astrocytes, the cytokines and chemokines they produce, and the influence of peripheral neuro-immune interactions, T cells, monocytes, complement proteins, acute phase proteins, oxidative injury, and related molecular processes. Neuroinflammation is a rapidly expanding field that has significantly enhanced our knowledge of chronic neurological diseases. It attracts researchers from diverse disciplines such as pathology, biochemistry, molecular biology, genetics, clinical medicine, and epidemiology. Substantial contributions to this field have been made through studies involving populations, patients, postmortem tissues, animal models, and in vitro systems. The Journal of Neuroinflammation consolidates research that centers around common pathogenic processes. It serves as a platform for integrative reviews and commentaries in this field.
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