炎症、调节和自噬的共表达模块和枢纽基因是人类脑出血外周免疫反应的基础。

BACKGROUND: Intracerebral hemorrhage (ICH) has a high morbidity and mortality. The peripheral immune system and cross-talk between peripheral blood and brain have been implicated in the ICH immune response. Thus, we delineated the gene networks associated with human ICH in the peripheral blood transcriptome. We also compared the differentially expressed genes in blood following ICH to a prior human study of perihematomal brain tissue. METHODS: We performed peripheral blood whole-transcriptome analysis of ICH and matched vascular risk factor control subjects (n = 66). Gene co-expression network analysis identified groups of co-expressed genes (modules) associated with ICH and their most interconnected genes (hubs). Mixed-effects regression identified differentially expressed genes in ICH compared to controls. RESULTS: Of seven ICH-associated modules, six were enriched with cell-specific genes: one neutrophil module, one neutrophil plus monocyte module, one T cell module, one Natural Killer cell module, and two erythroblast modules. The neutrophil/monocyte modules were enriched in inflammatory/immune pathways; the T cell module in T cell receptor signaling genes; and the Natural Killer cell module in genes regulating alternative splicing, epigenetic, and post-translational modifications. One erythroblast module was enriched in autophagy pathways implicated in experimental ICH, and NRF2 signaling implicated in hematoma clearance. Many hub genes or module members, such as IARS, mTOR, S1PR1, LCK, FYN, SKAP1, ITK, AMBRA1, NLRC4, IL6R, IL17RA, GAB2, MXD1, PIK3CD, NUMB, MAPK14, DDX24, EVL, TDP1, ATG3, WDFY3, GSK3B, STAT3, STX3, CSF3R, PIP4K2A, ANXA3, DGAT2, LRP10, FLOT2, ANK1, CR1, SLC4A1, and DYSF, have been implicated in neuroinflammation, cell death, transcriptional regulation, and some as experimental ICH therapeutic targets. Gene-level analysis revealed 1225 genes (FDR p < 0.05, fold-change > |1.2|) have altered expression in ICH in peripheral blood. There was significant overlap of the 1225 genes with dysregulated genes in human perihematomal brain tissue (p = 7 × 10). Overlapping genes were enriched for neutrophil-specific genes (p = 6.4 × 10) involved in interleukin, neuroinflammation, apoptosis, and PPAR signaling. CONCLUSIONS: This study delineates key processes underlying ICH pathophysiology, complements experimental ICH findings, and the hub genes significantly expand the list of novel ICH therapeutic targets. The overlap between blood and brain gene responses underscores the importance of examining blood-brain interactions in human ICH.

背景：脑出血（ICH）具有高发病率和死亡率。外周免疫系统以及外周血与大脑之间的串扰与 ICH 的免疫反应有关。因此，我们描绘了与人类 ICH 相关的外周血转录组中的基因网络。我们还将 ICH 后血液中差异表达的基因与先前的人类血肿周围脑组织研究进行了比较。

方法：我们对 ICH 患者和匹配的血管风险因素对照者（n=66）进行了外周血全转录组分析。基因共表达网络分析确定了与 ICH 相关的共表达基因（模块）及其最相互连接的基因（枢纽基因）。混合效应回归确定了与对照组相比，ICH 中差异表达的基因。

结果：在七个与 ICH 相关的模块中，有六个模块富含细胞特异性基因：一个中性粒细胞模块、一个中性粒细胞加单核细胞模块、一个 T 细胞模块、一个自然杀伤细胞模块和两个成红细胞模块。中性粒细胞/单核细胞模块富含炎症/免疫途径；T 细胞模块富含 T 细胞受体信号基因；自然杀伤细胞模块富含调节选择性剪接、表观遗传和翻译后修饰的基因。一个成红细胞模块富含实验性 ICH 中涉及的自噬途径以及与血肿清除有关的 NRF2 信号。许多枢纽基因或模块成员，如 IARS、mTOR、S1PR1、LCK、FYN、SKAP1、ITK、AMBRA1、NLRC4、IL6R、IL17RA、GAB2、MXD1、PIK3CD、NUMB、MAPK14、DDX24、EVL、TDP1、ATG3、WDFY3、GSK3B、STAT3、STX3、CSF3R、PIP4K2A、ANXA3、DGAT2、LRP10、FLOT2、ANK1、CR1、SLC4A1 和 DYSF，已被牵连到神经炎症、细胞死亡、转录调控中，其中一些是实验性 ICH 的治疗靶点。基因水平分析显示，1225 个基因（FDR p<0.05，倍数变化> |1.2|）在外周血中的 ICH 表达发生改变。与人类血肿周围脑组织中失调基因有显著重叠（p=7×10）。重叠基因富含中性粒细胞特异性基因（p=6.4×10），涉及白细胞介素、神经炎症、细胞凋亡和 PPAR 信号。

结论：本研究描绘了 ICH 病理生理学的关键过程，补充了实验性 ICH 的发现，枢纽基因显著扩展了新的 ICH 治疗靶点的列表。血液和大脑基因反应的重叠强调了研究人类 ICH 中血液-大脑相互作用的重要性。