Ablation of Type-1 IFN Signaling in Hematopoietic Cells Confers Protection Following Traumatic Brain Injury
Ablation of Type-1 IFN Signaling in Hematopoietic Cells Confers Protection Following Traumatic Brain Injury
复制标题
DOI：
10.1523/eneuro.0128-15.2016
复制
发表时间：
2016-01-01
期刊：
影响因子：
3.4
通讯作者：
Crack, Peter J.
中科院分区：
文献类型：
--
作者：
Karve, Ila P.;Zhang, Moses;Crack, Peter J.
1型干扰素（IFN）是通过1型IFN受体（IFNAR 1）发出信号的多效性细胞因子。最近的文献表明1型IFN与CNS疾病有关。在这项研究中，我们研究了1型干扰素在创伤性脑损伤（TBI）后神经炎症中的作用。使用受控的皮质撞击模型，在8至10周龄的雄性C57 BL/6 J WT和IFNAR 1（-/-）小鼠中诱导TBI，并切除脑以研究梗死体积、通过定量PCR分析的炎性介质释放和通过免疫组织化学的免疫细胞谱。与WT小鼠相比，IFNAR 1（-/-）小鼠在TBI后表现出较小的梗死。与WT小鼠相比，IFNAR 1（-/-）小鼠表现出改变的抗炎环境，TBI后促炎介质TNF α、IL-1 β和IL-6的水平显著降低，抗炎介质IL-10的上调以及常驻和外周免疫细胞的活化增加。WT小鼠在TBI前1 h、TBI后30 min或TBI后30 min和TBI后2 d静脉注射抗IFNAR 1阻断单克隆抗体（MAR 1），显示出显著改善的组织学和行为结果。骨髓嵌合体表明造血细胞是1型IFN的外周来源，其驱动神经炎症和恶化的TBI结果。1型干扰素mRNA水平被证实是显着改变，在人死后TBI的大脑。总之，这些数据表明，1型IFN信号传导是神经炎症进展中的关键途径，并为TBI的治疗提供了可行的治疗靶点。
Type-1 interferons (IFNs) are pleiotropic cytokines that signal through the type-1 IFN receptor (IFNAR1). Recent literature has implicated the type-1 IFNs in disorders of the CNS. In this study, we have investigated the role of type-1 IFNs in neuroinflammation following traumatic brain injury (TBI). Using a controlled cortical impact model, TBI was induced in 8-to 10-week-old male C57BL/6J WT and IFNAR1(-/-) mice and brains were excised to study infarct volume, inflammatory mediator release via quantitative PCR analysis and immune cell profile via immunohistochemistry. IFNAR1(-/-) mice displayed smaller infarcts compared with WT mice after TBI. IFNAR1(-/-) mice exhibited an altered anti-inflammatory environment compared with WT mice, with significantly reduced levels of the proinflammatory mediators TNF alpha, IL-1 beta and IL-6, an up-regulation of the anti-inflammatory mediator IL-10 and an increased activation of resident and peripheral immune cells after TBI. WT mice injected intravenously with an anti-IFNAR1 blocking monoclonal antibody (MAR1) 1 h before, 30 min after or 30 min and 2 d after TBI displayed significantly improved histological and behavioral outcome. Bone marrow chimeras demonstrated that the hematopoietic cells are a peripheral source of type-1 IFNs that drives neuroinflammation and a worsened TBI outcome. Type-1 IFN mRNA levels were confirmed to be significantly altered in human postmortem TBI brains. Together, these data demonstrate that type-1 IFN signaling is a critical pathway in the progression of neuroinflammation and presents a viable therapeutic target for the treatment of TBI.