DataSheet_1_Microglia shield the murine brain from damage mediated by the cytokines IL-6 and IFN-α.pdf

Sustained production of elevated levels of the cytokines interleukin (IL)-6 or interferon (IFN)-α in the central nervous system (CNS) is detrimental and directly contributes to the pathogenesis of neurological diseases such as neuromyelitis optica spectrum disorders or cerebral interferonopathies, respectively. Using transgenic mice with CNS-targeted production of IL-6 (GFAP-IL6) or IFN-α (GFAP-IFN), we have recently demonstrated that microglia are prominent target and effector cells and mount stimulus-specific responses to these cytokines. In order to further clarify the phenotype and function of these cells, we treated GFAP-IL6 and GFAP-IFN mice with the CSF1R inhibitor PLX5622 to deplete microglia. We examined their ability to recover from acute microglia depletion, as well as the impact of chronic microglia depletion on the progression of disease. Following acute depletion in the brains of GFAP-IL6 mice, microglia repopulation was enhanced, while in GFAP-IFN mice, microglia did not repopulate the brain. Furthermore, chronic CSF1R inhibition was detrimental to the brain of GFAP-IL6 and GFAP-IFN mice and gave rise to severe CNS calcification which strongly correlated with the absence of microglia. In addition, PLX5622-treated GFAP-IFN mice had markedly reduced survival. Our findings provide evidence for novel microglia functions to protect against IFN-α-mediated neurotoxicity and neuronal dysregulation, as well as restrain calcification as a result of both IL-6- and IFN-α-induced neuroinflammation. Taken together, we demonstrate that CSF1R inhibition may be an undesirable target for therapeutic treatment of neuroinflammatory diseases that are driven by elevated IL-6 and IFN-α production.

中枢神经系统（CNS）中持续高水平产生的细胞因子白细胞介素-6（IL-6）或干扰素-α（IFN-α）均具有有害作用，且分别直接参与视神经脊髓炎谱系疾病或大脑干扰素病的发病过程。本研究利用中枢神经系统靶向表达IL-6的（GFAP-IL6）或IFN-α的（GFAP-IFN）转基因小鼠，近期证实小胶质细胞（microglia）是主要的靶细胞与效应细胞，并能对这些细胞因子产生刺激特异性应答。为进一步阐明此类细胞的表型与功能，我们使用集落刺激因子1受体（CSF1R）抑制剂PLX5622处理GFAP-IL6与GFAP-IFN小鼠，以清除小胶质细胞。我们检测了小鼠在急性小胶质细胞清除后的恢复能力，以及慢性小胶质细胞清除对疾病进程的影响。在GFAP-IL6小鼠的大脑中实施急性小胶质细胞清除后，小胶质细胞的脑内定植重建能力增强；而在GFAP-IFN小鼠中，小胶质细胞无法在大脑内实现定植重建。此外，慢性CSF1R抑制对GFAP-IL6与GFAP-IFN小鼠的大脑均具有有害作用，可引发严重的中枢神经系统钙化，该现象与小胶质细胞的缺失高度相关。此外，经PLX5622处理的GFAP-IFN小鼠生存率显著降低。本研究结果证实小胶质细胞具有全新功能：可抵御IFN-α介导的神经毒性与神经元功能失调，并能抑制IL-6及IFN-α诱导的神经炎症所引发的钙化。综上，本研究证实，对于IL-6与IFN-α水平升高所驱动的神经炎症性疾病，CSF1R抑制或许并非理想的治疗靶点。