Abstract
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 (CD4creposgp130loxP/loxP) and macrophage/neutrophil-specific gp130-deficient (LysMcreposgp130loxP/loxP) mice with the myelin-oligodendrocyte-glycoprotein peptide MOG35–55. Whereas inflammatory immune responses, TH17 differentiation, and pathology in CD4creposgp130loxP/loxP mice were mitigated, disease progression was eventually enhanced in LysMcreposgp130loxP/loxP mice. Exacerbated disease in MOG35–55-immunized LysMcreposgp130loxP/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 LysMcreposIL-6RloxP/loxP mice. In contrast to LysMcreposgp130loxP/loxP mice, neuropathology in MOG35–55-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.
Highlights
Multiple sclerosis (MS) is one of the most common neurological diseases worldwide
Mice Are Resistant to EAE Induction gp130 cytokines like IL-6 and IL-27 induce different mechanisms in various cell types
Whereas IL-6 promotes the differentiation of CD4+ T cells to TH17 cells, IL-27 suppresses TH17 development of CD4+ T cells
Summary
Multiple sclerosis (MS) is one of the most common neurological diseases worldwide. It is well documented that MS represents an inflammatory demyelinating disease of the central nervous system (CNS) which is mediated by pathogenic CD4+ T helper (H) cells [1]. Using the animal model for MS known as experimental autoimmune encephalomyelitis (EAE), recent studies could show that autoreactive myelin-specific TH17 cells are responsible for the induction and maintenance of neuroinflammation whereas regulatory T cells (Treg) represent the most relevant cell line with respect to EAE resistance [2] Named for their ability to produce interleukin (IL)-17A and IL-17F, TH17 cells are crucial for the amplification of neuroinflammation by activating epithelial cells and attracting other immune cells because of their ability to express additional pro-inflammatory mediators such as tumor necrosis factor (TNF), granulocyte colony stimulating factor, granulocyte macrophage colony stimulating factor, IL-21, or IL-22 [3, 4]. To further analyze macrophage/neutrophil-specific effects on neuropathology mediated by IL-6, we included immunized LysMcreposIL-6RloxP/loxP mice
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