Intrastriatal injection of interleukin-1 beta triggers the formation of neuromyelitis optica-like lesions in NMO-IgG seropositive rats.
Intrastriatal injection of interleukin-1 beta triggers the formation of neuromyelitis optica-like lesions in NMO-IgG seropositive rats.
复制标题
纹状体内注射白介素-1ββ触发了NMO-IGG血清阳性大鼠的神经霉素类似神经瘤性病变的形成。
DOI：
10.1186/2051-5960-1-5
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发表时间：
2013-05-08
影响因子：
7.1
通讯作者：
Bradl M
中科院分区：
文献类型：
--
作者：
Kitic M;Hochmeister S;Wimmer I;Bauer J;Misu T;Mader S;Reindl M;Fujihara K;Lassmann H;Bradl M
视神经脊髓炎(NMO)是一种严重的中枢神经系统(CNS)疾病，其特征是在脊髓和视神经形成以星形胶质细胞为破坏性的、以中性粒细胞为主的炎性病变。这些损害是由致病性水通道蛋白4(AQP4)特异性自身抗体与星形胶质细胞结合并随后补体介导的这些细胞的裂解而开始的。通常，这些损害形成在中枢神经系统炎症的环境中，血脑屏障为抗体和补体的进入开放。然而，目前尚不清楚促炎细胞因子和趋化因子在多大程度上促进了NMO病变的形成。为了解决这个问题，我们将细胞因子IL-1β、肿瘤坏死因子α、IL-6、干扰素-γ和趋化因子CXCL2注射到NMO-IgG血清阳性大鼠的纹状体内，并在24小时后对组织进行免疫组织化学分析。所有注射的细胞因子和趋化因子都导致免疫球蛋白大量渗入注射侧大脑半球，但只有白细胞介素1β导致血管周围和中性粒细胞浸润性病变的形成，AQP4丢失和补体介导的星形胶质细胞破坏远离针道。用白介素1β处理大鼠脑内皮细胞，但不用任何其他细胞因子或趋化因子在相同浓度和相同时间内应用，可引起粒细胞募集和支持分子的显著上调。与任何其他细胞因子相比，注射白介素1β可导致血管周围血管数量和细胞C1q反应性增加。最后，对来自NMO和多发性硬化症患者的大样本中枢神经系统病变的筛查发现，在活动期NMO病变中有大量IL-1β反应的巨噬细胞/激活的小胶质细胞，而在具有相似病变活动和部位的MS病变中则没有。我们的数据有力地表明，在NMO损伤中释放的IL-1β和IL-1β诱导的补体因子(如C1q)的产生/积累促进了NMO损伤周围的中性粒细胞进入和BBB的破坏，因此可能是NMO损伤形成的一个重要的次要因素，可能是通过为NMO损伤的快速生长和放大的免疫细胞募集到该部位铺平基础。
Neuromyelitis optica (NMO) is a severe, disabling disease of the central nervous system (CNS) characterized by the formation of astrocyte-destructive, neutrophil-dominated inflammatory lesions in the spinal cord and optic nerves. These lesions are initiated by the binding of pathogenic aquaporin 4 (AQP4)-specific autoantibodies to astrocytes and subsequent complement-mediated lysis of these cells. Typically, these lesions form in a setting of CNS inflammation, where the blood–brain barrier is open for the entry of antibodies and complement. However, it remained unclear to which extent pro-inflammatory cytokines and chemokines contribute to the formation of NMO lesions. To specifically address this question, we injected the cytokines interleukin-1 beta, tumor necrosis factor alpha, interleukin-6, interferon gamma and the chemokine CXCL2 into the striatum of NMO-IgG seropositive rats and analyzed the tissue 24 hours later by immunohistochemistry. All injected cytokines and chemokines led to profound leakage of immunoglobulins into the injected hemisphere, but only interleukin-1 beta induced the formation of perivascular, neutrophil-infiltrated lesions with AQP4 loss and complement-mediated astrocyte destruction distant from the needle tract. Treatment of rat brain endothelial cells with interleukin-1 beta, but not with any other cytokine or chemokine applied at the same concentration and over the same period of time, caused profound upregulation of granulocyte-recruiting and supporting molecules. Injection of interleukin-1 beta caused higher numbers of blood vessels with perivascular, cellular C1q reactivity than any other cytokine tested. Finally, the screening of a large sample of CNS lesions from NMO and multiple sclerosis patients revealed large numbers of interleukin-1 beta-reactive macrophages/activated microglial cells in active NMO lesions but not in MS lesions with comparable lesion activity and location. Our data strongly suggest that interleukin-1 beta released in NMO lesions and interleukin-1 beta-induced production/accumulation of complement factors (like C1q) facilitate neutrophil entry and BBB breakdown in the vicinity of NMO lesions, and might thus be an important secondary factor for lesion formation, possibly by paving the ground for rapid lesion growth and amplified immune cell recruitment to this site.