Abstract
BackgroundInterleukin 23 is a critical cytokine in the pathogenesis of multiple sclerosis. But the local impact of interleukin 23 on the course of neuroinflammation is still not well defined. To further characterize the effect of interleukin 23 on CNS inflammation, we recently described a transgenic mouse model with astrocyte-specific expression of interleukin 23 (GF-IL23 mice). The GF-IL23 mice spontaneously develop a progressive ataxic phenotype with cerebellar tissue destruction and inflammatory infiltrates with high amounts of B cells most prominent in the subarachnoid and perivascular space.MethodsTo further elucidate the local impact of the CNS-specific interleukin 23 synthesis in autoimmune neuroinflammation, we induced a MOG35-55 experimental autoimmune encephalomyelitis (EAE) in GF-IL23 mice and WT mice and analyzed the mice by histology, flow cytometry, and transcriptome analysis.ResultsWe were able to demonstrate that local interleukin 23 production in the CNS leads to aggravation and chronification of the EAE course with a severe paraparesis and an ataxic phenotype. Moreover, enhanced multilocular neuroinflammation was present not only in the spinal cord, but also in the forebrain, brainstem, and predominantly in the cerebellum accompanied by persisting demyelination. Thereby, interleukin 23 creates a pronounced proinflammatory response with accumulation of leukocytes, in particular B cells, CD4+ cells, but also γδ T cells and activated microglia/macrophages. Furthermore, transcriptome analysis revealed an enhanced proinflammatory cytokine milieu with upregulation of lymphocyte activation markers, co-stimulatory markers, chemokines, and components of the complement system.ConclusionTaken together, the GF-IL23 model allowed a further breakdown of the different mechanisms how IL-23 drives neuroinflammation in the EAE model and proved to be a useful tool to further dissect the impact of interleukin 23 on neuroinflammatory models.
Highlights
Interleukin 23 is a critical cytokine in the pathogenesis of multiple sclerosis
central nervous system (CNS)-restricted expression of Interleukin 23 (IL-23) leads to a severe and chronic course of the EAE To further investigate how the CNS-restricted expression of IL-23 influence the clinical course of the EAEmodel as an animal model of Multiple sclerosis (MS), GF-IL23 mice and WT were immunized with MOG35-55 at an age of 2 months
GF-IL23 mice developed a progressive ataxic phenotype, which prompted us to use an additional score for ataxia to monitor these mice more accurately
Summary
Interleukin 23 is a critical cytokine in the pathogenesis of multiple sclerosis. To further characterize the effect of interleukin 23 on CNS inflammation, we recently described a transgenic mouse model with astrocyte-specific expression of interleukin 23 (GF-IL23 mice). The GF-IL23 mice spontaneously develop a progressive ataxic phenotype with cerebellar tissue destruction and inflammatory infiltrates with high amounts of B cells most prominent in the subarachnoid and perivascular space. Multiple sclerosis (MS) is the most common autoimmune disease of the central nervous system (CNS) and the most common disabling neurological disease of the young adulthood. B cell and plasma cell accumulation in perivascular lesions and in the subarachnoid space as well as leptomeningeal inflammation with ectopic lymphoid follicles were described in several studies [3,4,5]. Immunotherapies targeting B cells have been successful and approved in the treatment for relapsing-remitting MS patients and for progressive MS patients [6]
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