IL-1β enables CNS access to CCR2hi monocytes and the generation of pathogenic cells through GM-CSF released by CNS endothelial cells
IL-1β enables CNS access to CCR2hi monocytes and the generation of pathogenic cells through GM-CSF released by CNS endothelial cells
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DOI：
10.1073/pnas.1714948115
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发表时间：
2018-02-06
影响因子：
11.1
通讯作者：
Lacroix, Steve
中科院分区：
文献类型：
--
作者：
Pare, Alexandre;Mailhot, Benoit;Lacroix, Steve
限制致病性CNS炎症的分子干预用于治疗自身免疫性疾病，如多发性硬化症（MS）。值得注意的是，IL-1 β基因敲除小鼠对实验性自身免疫性脑脊髓炎（EAE），MS的动物模型具有高度抗性。在这里，我们表明，干扰IL-1 β/IL-1 R1轴严重损害了髓系细胞穿过中枢神经系统（CNS）内皮细胞（EC）的迁移。值得注意的是，我们报道炎症性CCR 2（hi）单核细胞表达IL-1 β有利于它们在EAE发作前进入脊髓。在用IL-1 β激活后，CNS EC释放GM-CSF，GM-CSF进而将单核细胞转化为抗原呈递细胞（APC）。因此，脊髓浸润的单核细胞来源的APC与分裂的CD 4（+）T细胞相关。从IL-1 β-感受态髓样细胞和CD 4（+）T细胞之间的相互作用释放的因子对神经元具有高度毒性。总之，我们的研究结果表明，IL-1 β信号转导是一个切入点，针对启动和恶化的神经炎症。
Molecular interventions that limit pathogenic CNS inflammation are used to treat autoimmune conditions such as multiple sclerosis (MS). Remarkably, IL-1 beta-knockout mice are highly resistant to experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Here, we show that interfering with the IL-1 beta/IL-1R1 axis severely impairs the transmigration of myeloid cells across central nervous system (CNS) endothelial cells (ECs). Notably, we report that IL-1 beta expression by inflammatory CCR2(hi) monocytes favors their entry into the spinal cord before EAE onset. Following activation with IL-1 beta, CNS ECs release GM-CSF, which in turn converts monocytes into antigen-presenting cells (APCs). Accordingly, spinal cord-infiltrated monocyte-derived APCs are associated with dividing CD4(+) T cells. Factors released from the interaction between IL-1 beta-competent myeloid cells and CD4(+) T cells are highly toxic to neurons. Together, our results suggest that IL-1 beta signaling is an entry point for targeting both the initiation and exacerbation of neuroinflammation.