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Antimicrobial protein REG3A and signaling networks are predictive of stroke outcomes
Journal of Neurochemistry ( IF 4.2 ) Pub Date : 2021-09-24 , DOI: 10.1111/jnc.15520 Madison Sands 1 , Jacqueline A Frank 1, 2 , Benton Maglinger 1 , Christopher J McLouth 3 , Amanda L Trout 1, 2 , Jadwiga Turchan-Cholewo 1, 2 , Ann M Stowe 1, 2, 4 , Justin F Fraser 1, 2, 4, 5, 6 , Keith R Pennypacker 1, 2, 4
Journal of Neurochemistry ( IF 4.2 ) Pub Date : 2021-09-24 , DOI: 10.1111/jnc.15520 Madison Sands 1 , Jacqueline A Frank 1, 2 , Benton Maglinger 1 , Christopher J McLouth 3 , Amanda L Trout 1, 2 , Jadwiga Turchan-Cholewo 1, 2 , Ann M Stowe 1, 2, 4 , Justin F Fraser 1, 2, 4, 5, 6 , Keith R Pennypacker 1, 2, 4
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Regenerating Family Member 3 Alpha (REG3A) is a multifunctional protein with antimicrobial activity, and primarily secreted by the intestine and pancreas. Studies have shown an increased expression of REG3A in systemic inflammatory responses to acute injury and infection, but studies investigating REG3A during the pathogenesis of ischemic stroke are limited. The aims of this study were to examine the associations between arterial expression of REG3A and other arterial inflammatory proteins implicated in stroke pathogenesis, as well as associations between REG3A and markers of poor outcome for ischemic stroke. The University of Kentucky Blood and Clot Thrombectomy Registry and Collaboration (BACTRAC) protocol (clinicaltrials.gov NCT03153683) utilizes thrombectomy to isolate intracranial arterial blood (i.e. distal to thrombus) and systemic arterial blood (i.e. carotid). Samples were analyzed by Olink Proteomics for N = 42 subjects. Statistical analyses of plasma proteins included 2-sample t-tests, spearman and biserial correlations, and robust regression models to elucidate network signaling and association to clinical outcomes. Results indicated that levels of systemic REG3A were positively correlated with inflammatory proteins interleukin IL6 (R = 0.344, p = 0.030) and IL17C (R = 0.468, p = 0.002). 2-sided t- tests examining differences of systemic REG3A within quartiles of NIHSS admission score depicted significant differences between quartiles. Those with NIHSS scores corresponding to moderate and moderate-severe neurofunctional deficits had significantly higher levels of systemic REG3A compared to those with NIHSS scores corresponding to mild and mild-moderate neurofunctional deficits (p = 0.016). STRING analyses of proteins in each robust regression model demonstrated substantial networking between REG3A and other systemic proteins highly relevant to ischemic stroke. The present study provides novel data on systemic REG3A in the context of ischemic stroke. These results demonstrate the influential role of REG3A regarding surrogate functional and radiographic outcomes of stroke severity. Additionally, they provide novel insight into the role of REG3A and related proteins during the complex neuroinflammatory process of ischemic stroke. These data provide a foundation for future studies to investigate REG3A and related networking proteins as potential biomarkers with prognostic potential, as well as potential therapeutic targets.
中文翻译：
抗菌蛋白 REG3A 和信号网络可预测中风结果
Regenerating Family Member 3 Alpha (REG3A) 是一种具有抗菌活性的多功能蛋白，主要由肠道和胰腺分泌。研究表明，REG3A 在对急性损伤和感染的全身炎症反应中表达增加，但在缺血性中风的发病机制中研究 REG3A 的研究是有限的。本研究的目的是检查 REG3A 的动脉表达与其他与中风发病机制有关的动脉炎症蛋白之间的关联，以及 REG3A 与缺血性中风预后不良标志物之间的关联。肯塔基大学血液和凝块血栓切除术注册与协作 (BACTRAC) 协议 (clinicaltrials.gov NCT03153683) 利用血栓切除术分离颅内动脉血（即 血栓远端）和全身动脉血（即颈动脉）。样本由 Olink Proteomics 分析N = 42 名受试者。血浆蛋白的统计分析包括 2 样本 t 检验、spearman 和双序列相关性，以及用于阐明网络信号和与临床结果关联的稳健回归模型。结果表明全身 REG3A 水平与炎症蛋白白细胞介素 IL6 ( R = 0.344, p = 0.030) 和 IL17C ( R = 0.468, p = 0.002）。检查 NIHSS 入学分数四分位数内系统性 REG3A 差异的双侧 t 检验描述了四分位数之间的显着差异。与 NIHSS 评分对应于轻度和轻中度神经功能缺陷的患者相比，NIHSS 评分对应于中度和中度至重度神经功能缺陷的患者具有显着更高水平的系统性 REG3A（p = 0.016）。在每个稳健的回归模型中对蛋白质的 STRING 分析表明 REG3A 和其他与缺血性中风高度相关的系统蛋白质之间存在大量网络。本研究提供了关于缺血性中风背景下系统性 REG3A 的新数据。这些结果证明了 REG3A 在中风严重程度的替代功能和影像学结果方面的影响作用。此外，它们为 REG3A 和相关蛋白在缺血性中风的复杂神经炎症过程中的作用提供了新的见解。这些数据为未来研究 REG3A 和相关网络蛋白作为具有预后潜力的潜在生物标志物以及潜在治疗靶点的研究奠定了基础。
更新日期：2021-09-24
中文翻译：
抗菌蛋白 REG3A 和信号网络可预测中风结果
Regenerating Family Member 3 Alpha (REG3A) 是一种具有抗菌活性的多功能蛋白，主要由肠道和胰腺分泌。研究表明，REG3A 在对急性损伤和感染的全身炎症反应中表达增加，但在缺血性中风的发病机制中研究 REG3A 的研究是有限的。本研究的目的是检查 REG3A 的动脉表达与其他与中风发病机制有关的动脉炎症蛋白之间的关联，以及 REG3A 与缺血性中风预后不良标志物之间的关联。肯塔基大学血液和凝块血栓切除术注册与协作 (BACTRAC) 协议 (clinicaltrials.gov NCT03153683) 利用血栓切除术分离颅内动脉血（即 血栓远端）和全身动脉血（即颈动脉）。样本由 Olink Proteomics 分析N = 42 名受试者。血浆蛋白的统计分析包括 2 样本 t 检验、spearman 和双序列相关性，以及用于阐明网络信号和与临床结果关联的稳健回归模型。结果表明全身 REG3A 水平与炎症蛋白白细胞介素 IL6 ( R = 0.344, p = 0.030) 和 IL17C ( R = 0.468, p = 0.002）。检查 NIHSS 入学分数四分位数内系统性 REG3A 差异的双侧 t 检验描述了四分位数之间的显着差异。与 NIHSS 评分对应于轻度和轻中度神经功能缺陷的患者相比，NIHSS 评分对应于中度和中度至重度神经功能缺陷的患者具有显着更高水平的系统性 REG3A（p = 0.016）。在每个稳健的回归模型中对蛋白质的 STRING 分析表明 REG3A 和其他与缺血性中风高度相关的系统蛋白质之间存在大量网络。本研究提供了关于缺血性中风背景下系统性 REG3A 的新数据。这些结果证明了 REG3A 在中风严重程度的替代功能和影像学结果方面的影响作用。此外，它们为 REG3A 和相关蛋白在缺血性中风的复杂神经炎症过程中的作用提供了新的见解。这些数据为未来研究 REG3A 和相关网络蛋白作为具有预后潜力的潜在生物标志物以及潜在治疗靶点的研究奠定了基础。
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