The brain microvasculature is a primary mediator of interferon-α neurotoxicity in human cerebral interferonopathies.

Aicardi-Goutières syndrome (AGS) is an autoinflammatory disease characterized by aberrant interferon (IFN)-α production. The major cause of morbidity in AGS is brain disease, yet the primary source and target of neurotoxic IFN-α remain unclear. Here, we demonstrated that the brain was the primary source of neurotoxic IFN-α in AGS and confirmed the neurotoxicity of intracerebral IFN-α using astrocyte-driven Ifna1 misexpression in mice. Using single-cell RNA sequencing, we demonstrated that intracerebral IFN-α-activated receptor (IFNAR) signaling within cerebral endothelial cells caused a distinctive cerebral small vessel disease similar to that observed in individuals with AGS. Magnetic resonance imaging (MRI) and single-molecule ELISA revealed that central and not peripheral IFN-α was the primary determinant of microvascular disease in humans. Ablation of endothelial Ifnar1 in mice rescued microvascular disease, stopped the development of diffuse brain disease, and prolonged lifespan. These results identify the cerebral microvasculature as a primary mediator of IFN-α neurotoxicity in AGS, representing an accessible target for therapeutic intervention.

Strawberry notch homolog 2 regulates the response to interleukin-6 in the central nervous system.

BACKGROUND: The cytokine interleukin-6 (IL-6) modulates a variety of inflammatory processes and, context depending, can mediate either pro- or anti-inflammatory effects. Excessive IL-6 signalling in the brain is associated with chronic inflammation resulting in neurodegeneration. Strawberry notch homolog 2 (Sbno2) is an IL-6-regulated gene whose function is largely unknown. Here we aimed to address this issue by investigating the impact of Sbno2 disruption in mice with IL-6-mediated neuroinflammation. METHODS: Mice with germline disruption of Sbno2 (Sbno2-/-) were generated and crossed with transgenic mice with chronic astrocyte production of IL-6 (GFAP-IL6). Phenotypic, molecular and transcriptomic analyses were performed on tissues and primary cell cultures to clarify the role of SBNO2 in IL-6-mediated neuroinflammation. RESULTS: We found Sbno2-/- mice to be viable and overtly normal. By contrast GFAP-IL6 × Sbno2-/- mice had more severe disease compared with GFAP-IL6 mice. This was evidenced by exacerbated neuroinflammation and neurodegeneration and enhanced IL-6-responsive gene expression. Cell culture experiments on primary astrocytes from Sbno2-/- mice further showed elevated and sustained transcript levels of a number of IL-6 stimulated genes. Notably, despite enhanced disease in vivo and gene expression both in vivo and in vitro, IL-6-stimulated gp130 pathway activation was reduced when Sbno2 is disrupted. CONCLUSION: Based on these results, we propose a role for SBNO2 as a novel negative feedback regulator of IL-6 that restrains the excessive inflammatory actions of this cytokine in the brain.

The cytokines interleukin-6 and interferon-α induce distinct microglia phenotypes.

BACKGROUND: Elevated production of the cytokines interleukin (IL)-6 or interferon (IFN)-α in the central nervous system (CNS) is implicated in the pathogenesis of neurological diseases such as neuromyelitis optica spectrum disorders or cerebral interferonopathies, respectively. Transgenic mice with CNS-targeted chronic production of IL-6 (GFAP-IL6) or IFN-α (GFAP-IFN) recapitulate important clinical and pathological features of these human diseases. The activation of microglia is a prominent manifestation found both in the human diseases and in the transgenic mice, yet little is known about how this contributes to disease pathology. METHODS: Here, we used a combination of ex vivo and in situ techniques to characterize the molecular, cellular and transcriptomic phenotypes of microglia in GFAP-IL6 versus GFAP-IFN mice. In addition, a transcriptomic meta-analysis was performed to compare the microglia response from GFAP-IL6 and GFAP-IFN mice to the response of microglia in a range of neurodegenerative and neuroinflammatory disorders. RESULTS: We demonstrated that microglia show stimulus-specific responses to IL-6 versus IFN-α in the brain resulting in unique and extensive molecular and cellular adaptations. In GFAP-IL6 mice, microglia proliferated, had shortened, less branched processes and elicited transcriptomic and molecular changes associated with phagocytosis and lipid processing. In comparison, microglia in the brain of GFAP-IFN mice exhibited increased proliferation and apoptosis, had larger, hyper-ramified processes and showed transcriptomic and surface marker changes associated with antigen presentation and antiviral response. Further, a transcriptomic meta-analysis revealed that IL-6 and IFN-α both contribute to the formation of a core microglia response in animal models of neurodegenerative and neuroinflammatory disorders, such as Alzheimer's disease, tauopathy, multiple sclerosis and lipopolysaccharide-induced endotoxemia. CONCLUSIONS: Our findings demonstrate that microglia responses to IL-6 and IFN-α are highly stimulus-specific, wide-ranging and give rise to divergent phenotypes that modulate microglia responses in neuroinflammatory and neurodegenerative diseases.

Zika virus encephalitis in immunocompetent mice is dominated by innate immune cells and does not require T or B cells.

BACKGROUND: Until the end of the twentieth century, Zika virus (ZIKV) was thought to cause a mostly mild, self-limiting disease in humans. However, as the geographic distribution of ZIKV has shifted, so too has its pathogenicity. Modern-day ZIKV infection is now known to cause encephalitis, acute disseminated encephalomyelitis, and Guillain-Barré syndrome in otherwise healthy adults. Nevertheless, the underlying pathogenetic mechanisms responsible for this shift in virulence remain unclear. METHODS: Here, we investigated the contribution of the innate versus the adaptive immune response using a new mouse model involving intracranial infection of adult immunocompetent mice with a moderately low dose of ZIKV MR766. To determine the contribution of type I interferons (IFN-Is) and adaptive immune cells, we also studied mice deficient for the IFN-I receptor 1 (Ifnar1-/-) and recombination-activating gene 1 (Rag1-/-). RESULTS: We show that intracranial infection with ZIKV resulted in lethal encephalitis. In wild-type mice, ZIKV remained restricted predominantly to the central nervous system (CNS) and infected neurons, whereas astrocytes and microglia were spared. Histological and molecular analysis revealed prominent activation of resident microglia and infiltrating monocytes that were accompanied by an expression of pro-inflammatory cytokines. The disease was independent of T and B cells. Importantly, unlike peripheral infection, IFN-Is modulated but did not protect from infection and lethal disease. Lack of IFN-I signaling resulted in spread of the virus, generalized inflammatory changes, and accelerated disease onset. CONCLUSIONS: Using intracranial infection of immunocompetent wild-type mice with ZIKV, we demonstrate that in contrast to the peripheral immune system, the CNS is susceptible to infection and responds to ZIKV by initiating an antiviral immune response. This response is dominated by resident microglia and infiltrating monocytes and macrophages but does not require T or B cells. Unlike in the periphery, IFN-Is in the CNS cannot prevent the establishment of infection. Our findings show that ZIKV encephalitis in mice is dependent on the innate immune response, and adaptive immune cells play at most a minor role in disease pathogenesis.