MicroRNA-155 enhances T cell trafficking and antiviral effector function in a model of coronavirus-induced neurologic disease.
MicroRNA-155 enhances T cell trafficking and antiviral effector function in a model of coronavirus-induced neurologic disease.
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DOI：
10.1186/s12974-016-0699-z
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发表时间：
2016-09-07
影响因子：
9.3
通讯作者：
O'Connell RM
中科院分区：
文献类型：
--
作者：
Dickey LL;Worne CL;Glover JL;Lane TE;O'Connell RM
microRNA（miRNAs）是主要在转录后水平调节细胞基因表达的非编码RNA。我们试图研究miR-155在病毒诱导的神经炎症模型中的功能作用。通过颅内注射小鼠肝炎病毒（JHMV）的神经嗜性JHM株到C57 BL/6 miR-155+/+野生型（WT）小鼠或miR-155−/−小鼠中，诱导急性脑脊髓炎和免疫介导的脱髓鞘。在感染后确定的时间点评估发病率和死亡率、CNS中病毒载量和免疫细胞积聚以及脊髓脱髓鞘。从感染的小鼠收获的T细胞用于检查细胞溶解活性、细胞因子活性和某些趋化因子受体的表达。为了确定miR-155对运输的影响，将来自感染WT或miR-155−/−小鼠的T细胞过继转移到RAG 1 −/−小鼠中，并使用流式细胞术评估T细胞在CNS中的蓄积。使用Mantel-Cox对数秩检验或Student's T检验确定统计学显著性。与WT小鼠相比，JHMV感染的miR-155−/−小鼠的疾病加重，伴随发病率/死亡率增加，并且无法控制CNS内的病毒复制。与疾病易感性增加相印证的是，miR-155−/−小鼠在数量、细胞溶解活性、IFN-γ分泌和归巢至CNS方面的CD 8 + T细胞应答减少，这与趋化因子受体CXCR 3的表达减少相对应。在miR-155−/−病毒特异性CD 4 + T细胞中，IFN-γ分泌和运输均受损;然而，在CD 4+细胞上分析的趋化因子归巢受体的表达不受影响。除了感染过程中的非常早期，WT和miR-155−/− JHMV感染的小鼠之间巨噬细胞浸润到CNS中没有显著差异，并且在感染后14天脱髓鞘的严重程度相似。在WT和miR-155−/− JHMV感染小鼠之间。这些发现支持miR-155在病毒诱导的脑脊髓炎模型中在宿主防御中的新作用。具体地，miR-155增强抗病毒T细胞应答，包括细胞因子分泌、细胞溶解活性和响应于病毒感染而归巢至CNS。此外，miR-155可以在神经炎症期间发挥宿主保护或宿主破坏作用，这取决于疾病触发因素。
MicroRNAs (miRNAs) are noncoding RNAs that modulate cellular gene expression, primarily at the post-transcriptional level. We sought to examine the functional role of miR-155 in a model of viral-induced neuroinflammation. Acute encephalomyelitis and immune-mediated demyelination were induced by intracranial injection with the neurotropic JHM strain of mouse hepatitis virus (JHMV) into C57BL/6 miR-155+/+ wildtype (WT) mice or miR-155−/− mice. Morbidity and mortality, viral load and immune cell accumulation in the CNS, and spinal cord demyelination were assessed at defined points post-infection. T cells harvested from infected mice were used to examine cytolytic activity, cytokine activity, and expression of certain chemokine receptors. To determine the impact of miR-155 on trafficking, T cells from infected WT or miR-155−/− mice were adoptively transferred into RAG1−/− mice, and T cell accumulation into the CNS was assessed using flow cytometry. Statistical significance was determined using the Mantel-Cox log-rank test or Student’s T tests. Compared to WT mice, JHMV-infected miR-155−/− mice developed exacerbated disease concomitant with increased morbidity/mortality and an inability to control viral replication within the CNS. In corroboration with increased susceptibility to disease, miR-155−/− mice had diminished CD8+ T cell responses in terms of numbers, cytolytic activity, IFN-γ secretion, and homing to the CNS that corresponded with reduced expression of the chemokine receptor CXCR3. Both IFN-γ secretion and trafficking were impaired in miR-155−/−, virus-specific CD4+ T cells; however, expression of the chemokine homing receptors analyzed on CD4+ cells was not affected. Except for very early during infection, there were not significant differences in macrophage infiltration into the CNS between WT and miR-155−/− JHMV-infected mice, and the severity of demyelination was similar at 14 days p.i. between WT and miR-155−/− JHMV-infected mice. These findings support a novel role for miR-155 in host defense in a model of viral-induced encephalomyelitis. Specifically, miR-155 enhances antiviral T cell responses including cytokine secretion, cytolytic activity, and homing to the CNS in response to viral infection. Further, miR-155 can play either a host-protective or host-damaging role during neuroinflammation depending on the disease trigger.
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