"Rogue" [DEspR+CD11b+] neutrophil subset correlates with severity in spontaneous intracerebral hemorrhage.
"Rogue" [DEspR+CD11b+] neutrophil subset correlates with severity in spontaneous intracerebral hemorrhage.
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DOI：
10.3389/fneur.2022.935579
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发表时间：
2022
影响因子：
3.4
通讯作者：
中科院分区：
文献类型：
--
作者：
累积的临床、细胞和分子证据加强了中性粒细胞在自发性脑出血(SICH)继发性脑损伤中的作用。然而，由于全身性中性粒细胞抑制是有害的，识别与SICH严重程度相关的靶向性“无赖”中性粒细胞亚群是关键。在一项对同意的SICH患者进行的先导性前瞻性观察研究中，我们对全血进行免疫分型，以评估循环中性粒细胞标志物：(A)流式细胞仪检测Despr±CD11b±中性粒细胞，(B)免疫荧光细胞学检测Despr±CD11b±中性粒细胞胞外陷阱(Net)形成中性粒细胞，以及(C)中性粒细胞/淋巴细胞比率(NLR)。使用Spearman等级相关(R)和Bonferroni校正，我们评估了中性粒细胞标志物与Sich严重程度、指数ICH评分、90天改良Rankin评分(MRS)以及潜在相互关系的当天临床和神经影像参数的相关性。作为对照，我们评估了SICH当天升高的血浆生物标志物：IL-6/IL-6、髓过氧化物酶/MPO、可溶性末端补体复合体/sC5b-9、内皮素-1/ET-1和线粒体/核DNA比率(mt/nDNA比率)。在90天MRS评分中，我们发现三种中性粒细胞标志物[r(n=13)>；0.71，POWER>；0.8，Bonferroni校正PB<；0.05]与90天MRS评分、Despr+CD11b+中性粒细胞计数、NLR与血肿周围水肿(PHE)体积以及Despr+CD11b+净形成中性粒细胞计数与实质内出血(IPH)-体积有很强的相关性。只有Despr+CD11b+中性粒细胞计数与ICH指数评分、当日格拉斯哥昏迷评分(GCS)评分、NLR和网织中性粒细胞计数有较强的相关性。脑出血评分与3项中性粒细胞标志物总和相关性最高[r(n=13)0.94，PB=10−5]。相反，除了MPO外，被测试的血浆生物标记物都升高了，但在这项初步研究中没有显示出相关性。与多种SICH严重程度测量、网络形成和NLR的强烈相关性表明，Despr+CD11b+中性粒细胞可能是SICH中的一种“无赖”中性粒细胞亚群。三种中性粒细胞标志物的总和和ICH评分与90天MRS结果的相关性更强，进一步证实了中性粒细胞介导的早期继发性脑损伤是SICH患者预后的关键决定因素。总之，这些数据为正式研究Despr+CD11b+中性粒细胞亚群作为中性粒细胞驱动的继发性脑损伤的潜在生物标志物提供了基础。数据还显示，对Sich中性粒细胞患者的体外分析是一个翻译里程碑，可以完善临床前研究和临床研究之间的假设。
Cumulative clinical, cellular, and molecular evidence reinforces the role of neutrophils in secondary brain injury in spontaneous intracerebral hemorrhage (sICH). However, since generalized neutrophil inhibition is detrimental, identification of targetable “rogue” neutrophil subsets associated with sICH severity is key. In a pilot prospective observational study of consented patients with sICH, we immunotyped whole blood to assess circulating neutrophil markers (~day 3 after ICH symptoms onset): (a) DEspR±CD11b± neutrophils by flow cytometry, (b) DEspR±CD11b± neutrophil extracellular trap (NET)-forming neutrophils by immunofluorescence cytology, and (c) neutrophil-lymphocyte ratio (NLR). Using Spearman rank correlation (r) with Bonferroni correction, we assessed the association of neutrophil markers with same-day clinical and neuroimaging parameters of sICH severity, index ICH score, 90-day modified Rankin Scale (mRS) score, and potential interrelationships. As comparators, we assessed same-day plasma biomarkers elevated in sICH: interleukin-6/IL-6, myeloperoxidase/MPO, soluble-terminal complement complex/sC5b-9, endothelin-1/ET-1, and mitochondrial/nuclear DNA ratio (mt/nDNA ratio). We detected strong correlations [r(n = 13) > 0.71, power > 0.8, Bonferroni corrected pB < 0.05] for all three neutrophil markers with 90-day mRS score, differentially for DEspR+CD11b+ neutrophil counts, and NLR with perihematomal edema (PHE) volume and for DEspR+CD11b+ NET-forming neutrophil counts with intraparenchymal hemorrhage (IPH)-volume. Only DEspR+CD11b+ neutrophil counts show a strong correlation with index ICH score, same-day Glasgow Coma Scale (GCS) score, and NLR and NET-forming neutrophil counts. The sum of the ICH score and three neutrophil markers exhibited the highest correlation: [r(n = 13) 0.94, pB = 10−5]. In contrast, plasma biomarkers tested were elevated except for MPO but exhibited no correlations in this pilot study. Strong correlation with multiple sICH severity measures, NET formation, and NLR identifies DEspR+CD11b+ neutrophils as a putative “rogue” neutrophil subset in sICH. The even stronger correlation of the sum of three neutrophil markers and the index ICH score with 90-day mRS outcome reinforces early neutrophil-mediated secondary brain injury as a key determinant of outcome in patients with sICH. Altogether, data provide a basis for the formal study of the DEspR+CD11b+ neutrophil subset as a potential actionable biomarker for neutrophil-driven secondary brain injury in sICH. Data also show ex vivo analysis of patients with sICH neutrophils as a translational milestone to refine hypotheses between preclinical and clinical studies.
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影响因子：
18.4
作者：
Eruslanov EB;Singhal S;Albelda SM
通讯作者：
Albelda SM
影响因子：
5.3
作者：
Ducruet, Andrew F.;Zacharia, Brad E.;Hickman, Zachary L.;Grobelny, Bartosz T.;Yeh, Mason L.;Sosunov, Sergey A.;Connolly, E. Sander, Jr.
通讯作者：
Connolly, E. Sander, Jr.
影响因子：
8.3
作者：
通讯作者：
--
影响因子：
168.9
作者：
Hanley, Daniel F.;Thompson, Richard E.;Awad, Issam A.
通讯作者：
Awad, Issam A.
早期增加的中性粒细胞与淋巴细胞比率与自发性脑出血的 3 个月预后不良相关
影响因子：
3.7
作者：
Qin, Jie;Li, Zhu;Xu, Yuming
通讯作者：
Xu, Yuming