Interferon-alpha Signaling in the Central Nervous System and Neuropsychiatric Lupus

Abstract

Sickness behaviors are ubiquitous experiences among all, whether it be through pathogenic infection, or sterile inflammatory events such as autoimmunity and cancer. While its severity can range from a mild headache to debilitating fatigue, there is universal recognition that sickness behaviors negatively impact on the quality of life. A wide variety of inflammatory mediators have been shown to play important roles in mediating sickness behavior, but in general the finer mechanisms are not well understood. Interferon-alpha (IFNα) is a classic inflammatory cytokine that is produced in response to a viral infection, and has also been implicated in various autoimmune diseases, most notably systemic lupus erythematosus (SLE). Because of the clear clinical evidence linking therapeutic IFNα in hepatitis C and melanoma patients with neuropsychiatric side effects, it is very likely that the neuropsychiatric sequelae observed in virally infected, and neuropsychiatric lupus (NPSLE) patients involve IFNα. Focusing on the effects of exogenously introduced IFNα in mice, we show that microglia in the brain respond by engulfing synapses selectively within specific brain regions, and that IFNα-mediated upregulation of complement component C4b could be an important driver of pathological synaptic pruning. We next validated a mouse model of NPSLE, showing clinically relevant SLE immune and neuropsychiatric phenotypes. Strikingly, we also show that the central nervous system (CNS) type 1 interferon response in this model is spatially restricted to patches of inflammatory gene expression. Our results support the integration of spatial variables in further investigations of inflammation and neuropsychiatric disease, and the therapeutic exploration of CNS targeted type 1 interferon modulators in NPSLE and other interferonopathies.