Impact of a Demyelination-Inducing Central Nervous System Virus on Expression of Demyelination Genes in Type 2 Lymphoid Cells.
Impact of a Demyelination-Inducing Central Nervous System Virus on Expression of Demyelination Genes in Type 2 Lymphoid Cells.
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脱髓鞘诱导中枢神经系统病毒对 2 型淋巴细胞脱髓鞘基因表达的影响。
DOI：
10.1128/jvi.01934-20
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发表时间：
2021
影响因子：
5.4
通讯作者：
Ghiasi,Homayon
中科院分区：
文献类型：
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作者：
Hirose,Satoshi;Kato,Mihoko;Tormanen,Kati;ShafieiJahani,Pedram;Akbari,Omid;Ghiasi,Homayon
我们最近报道了2型固有淋巴样细胞(ILC2s)在中枢神经系统(CNS)脱髓鞘中的作用，该模型采用了重组单纯疱疹病毒1型(HSV-1)并组成地表达小鼠白细胞介素2(HSV-IL-2)的CNS脱髓鞘模型。在这项研究中，我们利用细胞因子和基因表达谱在细胞水平上研究了ILC2细胞对HSV-IL-2的应答。感染HSV-IL-2的ILC2细胞表达的粒细胞-巨噬细胞集落刺激因子(GM-CSF)、IL-5、IL-6、IL-13、IP-10、MIP-2和RANTES均高于亲本对照病毒感染的ILC2。相反，单纯疱疹病毒IL-2感染后，ILC2细胞典型表达的TH2细胞因子IL-4和IL-9不被诱导。转录组测序(RNA-seq)分析表明，与亲本病毒感染的ILC2相比，HSV-IL-2感染的ILC2有350多个基因显著上调，157个基因下调。基因本体论(GO)术语分析表明，与“有丝分裂”和“炎症反应”相关的基因是上调的基因之一，提示HSV-IL-2感染驱动了ILC2s的过度增殖和非典型炎症反应。ILC2激活状态的这种变化可能是脱髓鞘疾病的病理基础。先天淋巴细胞具有可塑性，可以改变功能；2型固有淋巴样细胞(ILC2s)可以转化为ILC1或ILC3细胞或改变其激活状态，根据环境提示产生IL-17或IL-10。在这项研究中，我们研究了在HSV-IL-2诱导的中枢神经系统脱髓鞘过程中起主要作用的ILC2基因和细胞因子的变化。感染HSV-IL-2的ILC2细胞出现大量的细胞状态重塑。此外，感染HSV-IL-2的ILC2在细胞和病毒基因表达谱以及细胞因子/趋化因子诱导方面与亲本HSV感染的ILC2细胞不同，它们表现出更强的激活和促炎反应。ILC2激活状态的这些变化可能是脱髓鞘疾病的病理基础。这些结果还突显了病原体作为环境线索改变固有淋巴细胞功能的可能重要性。
We recently reported the role of type 2 innate lymphoid cells (ILC2s) in central nervous system (CNS) demyelination using a model of CNS demyelination involving recombinant herpes simplex virus 1 (HSV-1) that constitutively expresses mouse interleukin 2 (HSV-IL-2). In this investigation, we studied how ILC2s respond to HSV-IL-2 at the cellular level using cytokine and gene expression profiling. ILC2s infected with HSV-IL-2 expressed higher levels of granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-5, IL-6, IL-13, IP-10, MIP-2, and RANTES, which include proinflammatory cytokines, than did those infected with parental control virus. In contrast, TH2 cytokines IL-4 and IL-9, which are typically expressed by ILC2s, were not induced upon HSV-IL-2 infection. Transcriptome sequencing (RNA-seq) analysis of HSV-IL-2 infected ILC2s showed significant upregulation of over 350 genes and downregulation of 157 genes compared with parental virus-infected ILC2s. Gene Ontology (GO) term analysis indicated that genes related to “mitosis” and “inflammatory response” were among the upregulated genes, suggesting that HSV-IL-2 infection drives the excessive proliferation and atypical inflammatory response of ILC2s. This change in ILC2 activation state could underlie the pathology of demyelinating diseases.IMPORTANCEInnate lymphocytes have plasticity and can change functionality; type 2 innate lymphoid cells (ILC2s) can convert to ILC1 or ILC3 cells or change their activation state to produce IL-17 or IL-10 depending on environmental cues. In this study, we investigated the gene and cytokine profiles of ILC2s, which play a major role in HSV-IL-2-induced CNS demyelination. ILC2s infected with HSV-IL-2 displayed a massive remodeling of cellular state. Additionally, ILC2s infected with HSV-IL-2 differed from those infected with parental HSV in cellular and viral gene expression profiles and in cytokine/chemokine induction, and they displayed enhanced activation and proinflammatory responses. These changes in ILC2 activation state could underlie the pathology of demyelinating diseases. These results also highlight the possible importance of pathogens as environmental cues to modify innate lymphocyte functionalities.