Division of Infection Immunology, Research Center Borstel, Borstel, Germany.
Institute of Neuropathology, Medical Faculty University of Freiburg, Freiburg, Germany.
Front Immunol. 2018 May 2;9:836. doi: 10.3389/fimmu.2018.00836. eCollection 2018.
gp130 cytokines are differentially involved in regulating the T helper (H) 17-driven pathogenesis of experimental autoimmune encephalomyelitis (EAE), the animal model of human multiple sclerosis. Interleukin (IL)-6 directly promotes the development of TH17 cells through the gp130/IL-6R complex. By contrast, IL-27 has been shown to suppress a TH17 immune response by gp130/IL-27R-alpha (α) receptor ligation. The IL-27-dependent regulation of a TH17 development could be mediated on the level of CD4 T cells. However, because IL-27 also suppresses the secretion of the TH17-driving cytokines IL-6 and IL-12/23p40 in accessory cells, TH17 immune responses may also be controlled by IL-27 on the level of macrophages and/or neutrophils. To analyze these opposing effects of gp130 engagement on the pathogenesis of EAE, we immunized CD4 T cell-specific gp130-deficient (CD4cregp130) and macrophage/neutrophil-specific gp130-deficient (LysMcregp130) mice with the myelin-oligodendrocyte-glycoprotein peptide MOG. Whereas inflammatory immune responses, TH17 differentiation, and pathology in CD4cregp130 mice were mitigated, disease progression was eventually enhanced in LysMcregp130 mice. Exacerbated disease in MOG-immunized LysMcregp130 mice was associated with an elevated development of TH17 cells and increased infiltration of the central nervous system with leukocytes indicating a suppressive role of macrophage/neutrophil-gp130. To further prove IL-6 to be responsible for the control of inflammation during EAE through gp130 on macrophages/neutrophils, we immunized LysMcreIL-6R mice. In contrast to LysMcregp130 mice, neuropathology in MOG-immunized macrophage/neutrophil-specific IL-6R-deficient mice was not enhanced indicating that the alleviation of EAE through macrophage/neutrophil-gp130 is mediated independently of IL-6. Together, this different pathology in macrophage/neutrophil- and CD4 T cell-specific gp130-deficient mice suggests that gp130 cytokines modulate TH17 inflammation differentially by targeting distinct cell types.
gp130 细胞因子在调节实验性自身免疫性脑脊髓炎 (EAE) 的 TH17 驱动发病机制中具有差异作用，EAE 是人类多发性硬化症的动物模型。白细胞介素 (IL)-6 通过 gp130/IL-6R 复合物直接促进 TH17 细胞的发育。相比之下，IL-27 已被证明通过 gp130/IL-27R-α (α) 受体结合来抑制 TH17 免疫反应。IL-27 对 TH17 发育的调节作用可能在 CD4 T 细胞水平上进行。然而，因为 IL-27 也抑制辅助细胞中 TH17 驱动细胞因子 IL-6 和 IL-12/23p40 的分泌，TH17 免疫反应也可能受到巨噬细胞和/或中性粒细胞中 IL-27 的控制。为了分析 gp130 结合对 EAE 发病机制的这些相反影响，我们用髓鞘少突胶质细胞糖蛋白肽 MOG 免疫 CD4 T 细胞特异性 gp130 缺陷型 (CD4cregp130) 和巨噬细胞/中性粒细胞特异性 gp130 缺陷型 (LysMcregp130) 小鼠。虽然 CD4cregp130 小鼠的炎症免疫反应、TH17 分化和病理学得到缓解，但 LysMcregp130 小鼠的疾病进展最终增强。MOG 免疫的 LysMcregp130 小鼠中疾病加重与 TH17 细胞的发育增加以及中枢神经系统白细胞浸润增加有关，这表明巨噬细胞/中性粒细胞-gp130 具有抑制作用。为了进一步证明 IL-6 通过巨噬细胞/中性粒细胞上的 gp130 负责控制 EAE 期间的炎症，我们免疫了 LysMcreIL-6R 小鼠。与 LysMcregp130 小鼠相反，MOG 免疫的巨噬细胞/中性粒细胞特异性 IL-6R 缺陷型小鼠的神经病理学没有增强，表明通过巨噬细胞/中性粒细胞-gp130 缓解 EAE 不依赖于 IL-6。总之，巨噬细胞/中性粒细胞和 CD4 T 细胞特异性 gp130 缺陷型小鼠的不同病理学表明，gp130 细胞因子通过针对不同的细胞类型来调节 TH17 炎症。
