Immunoinflammatory diseases of the central nervous system - the tale of two cytokines

Abstract

Cytokines are potent mediators of cellular communication that have crucial roles in the regulation of innate and adaptive immunoinflammatory responses. Clear evidence has emerged in recent years that the dysregulated production of cytokines may in itself be causative in the pathogenesis of certain immunoinflammatory disorders. Here we review current evidence for the involvement of two different cytokines, IFN-α and IL-6, as principal mediators of specific immunoinflammatory disorders of the CNS. IFN-α belongs to the type I IFN family and is causally linked to the development of inflammatory encephalopathy exemplified by the genetic disorder, Aicardi-Goutières syndrome. IL-6 belongs to the gp130 family of cytokines and is causally linked to a number of immunoinflammatory disorders of the CNS including neuromyelitis optica, idiopathic transverse myelitis and genetically linked autoinflammatory neurological disease. In addition to clinical evidence, experimental studies, particularly in genetically engineered mouse models with astrocyte-targeted, CNS-restricted production of IFN-α or IL-6 replicate many of the cardinal neuropathological features of these human cytokine-linked immunoinflammatory neurological disorders giving crucial evidence for a direct causative role of these cytokines and providing further rationale for the therapeutic targeting of these cytokines in neurological diseases where indicated.

Figure 1

Pathways to IFN‐I‐mediated encephalopathy in mice and humans. In AGS, SLE encephalopathy or IBGC inactivating mutations occur in TREX1, RNASEH2, SAMHD1, ADAR1 or ISG15. AGS may also be caused by a gain‐of‐function mutation of the IFIH1 gene. These different mutations together with chronic viral infection of the CNS can lead to the inappropriate production of IFN‐α in the brain which then causes inflammatory encephalopathy with calcification and neurodegeneration. Many of the key neuropathological features of these human ‘interferonopathies’ are reproduced in GFAP‐IFNα transgenic mice with astrocyte‐targeted production of IFN‐α providing proof of principle that chronic elevation of IFN‐α in the brain may be a primary cause of disease in AGS.

Figure 2

IL‐6 as a causal factor in human neurological disease replicated in transgenic mice with astrocyte‐targeted production of IL‐6. Accumulating evidence reveals IL‐6 to be a key pathogenetic factor in a number of human neurological disorders including neuromyelitis optica, idiopathic transverse myelitis and autoinflammatory encephalopathy. It is likely that there will be other neurological conditions in which a role for IL‐6 is indicated. Formal experimental evidence of IL‐6 as a direct mediator of neurological disease has come from transgenic mice with astrocyte‐targeted production of murine IL‐6 in the brain. These GFAP‐IL6 mice develop a spectrum of progressive molecular and cellular alterations giving rise to abnormal electrophysiological and neuroendocrine function, as well as learning impairment and motor disease.