Interleukin-6-induced neuroinflammation is exacerbated by subclinical levels of interferon-α.

INTRODUCTION: Cerebral cytokinopathies are key examples of dysregulated cytokine responses. While mouse models with targeted production of individual cytokines have been pivotal in establishing a causal link between cytokines and disease- especially in the central nervous system-they often fail to replicate the complex inflammatory environments seen in various neuropathological conditions, such as neuromyelitis optica spectrum disorder, where multiple cytokines are upregulated. METHODS: To address this, we developed a novel mouse model, GFAP-IL6-IFN (lo) mice, by combining transgenic mice with astrocyte-targeted production of IL-6 (GFAP-IL6 mice) and IFN-α (GFAP-IFN (lo) mice). RESULTS: Our findings reveal that chronic, low-level production of IFN-α, below the typical disease-inducing threshold, significantly accelerates disease progression in GFAP-IL6-IFN (lo) mice compared to GFAP-IL6 mice. The double transgenic mice exhibited progressive ataxia, persistent seizure-like episodes, and reduced survival. Remarkably, the clinical and pathological symptoms remained predominantly IL-6-driven and required the presence of adaptive immune cells. CONCLUSION: In summary, we demonstrate that subclinical levels of IFN-α can markedly exacerbate IL-6-mediated neurological disease, suggesting that future studies, should consider the combined effects of IL-6 and IFN-α.