Differing Outcome of experimental autoimmune encephalitis in Macrophage/neutrophil- and T cell-specific gp130-Deficient Mice
Differing Outcome of experimental autoimmune encephalitis in Macrophage/neutrophil- and T cell-specific gp130-Deficient Mice
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DOI：
10.3389/fimmu.2018.00836
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发表时间：
2018-05-02
影响因子：
7.3
通讯作者：
Hoelscher, Christoph
中科院分区：
文献类型：
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作者：
Holz, Kristian;Prinz, Marco;Hoelscher, Christoph
gp130细胞因子在调节实验性自身免疫性脑脊髓炎（EAE）（人类多发性硬化症动物模型）的T辅助性(H) 17驱动的发病机制中存在差异。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)受体连接抑制TH17免疫应答。il -27依赖性的TH17发育调控可能在CD4 T细胞水平上介导。然而，由于IL-27也抑制TH17驱动细胞因子IL-6和IL-12/23p40在辅助细胞中的分泌，因此在巨噬细胞和/或中性粒细胞水平上，TH17免疫应答也可能由IL-27控制。为了分析gp130参与EAE发病机制的这些相反作用，我们用髓鞘-少鞘细胞糖蛋白肽MOG免疫CD4(+) T细胞特异性gp130缺陷(CD4cre（pos)gp130(loxP/loxP)）和巨噬细胞/中性粒细胞特异性gp130缺陷(LysMcre（pos)gp130(loxP/loxP)）小鼠（35-55）。虽然CD4cre(pos)gp130（loxP/loxP）小鼠的炎症免疫反应、TH17分化和病理得到缓解，但LysMcre(pos)gp130（loxP/loxP）小鼠的疾病进展最终得到加强。MOG（35-55）免疫的LysMcre(pos)gp130（loxP/loxP）小鼠疾病加重与TH17细胞发育升高和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gp130对巨噬细胞/中性粒细胞控制EAE期间的炎症，我们对LysMcre(pos)IL-6R（loxP/loxP）小鼠进行了免疫。与LysMcre(pos)gp130（loxP/loxP）小鼠相比，MOG（35-55）免疫巨噬细胞/中性粒细胞特异性il- 6r缺陷小鼠的神经病理学未增强，这表明巨噬细胞/中性粒细胞-gp130介导的EAE减轻不依赖于IL-6。总之，巨噬细胞/中性粒细胞和CD4 T细胞特异性gp130缺陷小鼠的这种不同病理表明，gp130细胞因子通过靶向不同的细胞类型来不同地调节TH17炎症。
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 (alpha) 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 (CD4cre(pos)gp130(loxP/loxP)) and macrophage/neutrophil-specific gp130-deficient (LysMcre(pos)gp130(loxP/loxP)) mice with the myelin-oligodendrocyte-glycoprotein peptide MOG(35-55). Whereas inflammatory immune responses, TH17 differentiation, and pathology in CD4cre(pos)gp130(loxP/loxP) mice were mitigated, disease progression was eventually enhanced in LysMcre(pos)gp130(loxP/loxP) mice. Exacerbated disease in MOG(35-55)-immunized LysMcre(pos)gp130(loxP/loxP) 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 LysMcre(pos)IL-6R(loxP/loxP) mice. In contrast to LysMcre(pos)gp130(loxP/loxP) mice, neuropathology in MOG(35-55)-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.