Interleukin-6 (IL-6) is a pleiotropic cytokine that controls numerous physiological processes both in basal and neuroinflammatory conditions, including the inflammatory response to experimental autoimmune encephalomyelitis (EAE). IL-6 is produced by multiple peripheral and central cells, and until now, the putative roles of IL-6 from different cell types have been evaluated through conditional cell-specific IL-6 knockout mice. Nevertheless, these mice probably undergo compensatory responses of IL-6 from other cells, which makes it difficult to assess the role of each source of IL-6. To give some insight into this problem, we have produced a novel mouse model: a conditional reversible IL-6 KO mouse (IL6-DIO-KO). By using double-inverted, open-reading-frame (DIO) technology, we created a mouse line with the loss of Il6 expression in all cells that can be restored by the action of Cre recombinase. Since microglia are one of the most important sources and targets of IL-6 into the central nervous system, we have recovered microglial Il6 expression in IL6-DIO-KO mice through breeding to Cx3cr1-CreER mice and subsequent injection of tamoxifen (TAM) when mice were 10–16 weeks old. Then, they were immunized with myelin oligodendrocyte glycoprotein 35-55 peptide (MOG35-55) 7 weeks after TAM treatment to induce EAE. Clinical symptoms and demyelination, CD3 infiltration, and gliosis in the spinal cord were evaluated. IL6-DIO-KO mice were resistant to EAE, validating the new model. Restoration of microglial Il6 was sufficient to develop a mild version of EAE-related clinical symptoms and neuropathology. IL6-DIO-KO mouse is an excellent model to understand in detail the role of specific cellular sources of IL-6 within a recovery-of-function paradigm in EAE.

中文翻译：

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一种以 Cre 依赖性方式研究白细胞介素 6 (IL-6) 表达恢复的新小鼠模型：小胶质细胞 IL-6 对实验性自身免疫性脑脊髓炎的调节

白细胞介素 6 (IL-6) 是一种多效性细胞因子，可控制基础和神经炎症条件下的许多生理过程，包括对实验性自身免疫性脑脊髓炎 (EAE) 的炎症反应。IL-6 由多个外周和中枢细胞产生，到目前为止，已经通过条件性细胞特异性 IL-6 敲除小鼠评估了来自不同细胞类型的 IL-6 的假定作用。然而，这些小鼠可能会​​经历来自其他细胞的 IL-6 的代偿反应，这使得评估每种 IL-6 来源的作用变得困难。为了深入了解这个问题，我们制作了一个新的小鼠模型：条件可逆 IL-6 KO 小鼠 (IL6-DIO-KO)。通过使用双倒置、开放阅读框 (DIO) 技术，我们创建了一个小鼠品系，所有细胞中 Il6 表达的缺失都可以通过 Cre 重组酶的作用恢复。由于小胶质细胞是 IL-6 进入中枢神经系统的最重要来源和靶点之一，我们通过与 Cx3cr1-CreER 小鼠的繁殖和随后注射他莫昔芬 (TAM) 恢复了 IL6-DIO-KO 小鼠中小胶质细胞 Il6 的表达。小鼠为 10-16 周大。然后，他们在 TAM 治疗后 7 周用髓鞘少突胶质细胞糖蛋白 35-55 肽 (MOG35-55) 进行免疫以诱导 EAE。评估了临床症状和脊髓中的脱髓鞘、CD3 浸润和神经胶质增生。IL6-DIO-KO 小鼠对 EAE 具有抗性，验证了新模型。小胶质细胞 Il6 的恢复足以产生与 EAE 相关的临床症状和神经病理学的轻度版本。