CNS-Specific Synthesis of Interleukin 23 Induces a Progressive Cerebellar Ataxia and the Accumulation of Both T and B Cells in the Brain: Characterization of a Novel Transgenic Mouse Model

Nitsch, Louisa; Zimmermann, Julian; Krauthausen, Marius; Höfer, Markus; Saggu, Raman; Petzold, Gabor C.; Heneka, Michael T.; Getts, Daniel R.; Becker, Albert; Campbell, Iain L.; Müller, Marcus

doi:10.1007/s12035-019-1640-0

Cited by 19 publications

(24 citation statements)

References 66 publications

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“…IL-23 is an essential cytokine in the development of MS. In our previous work, we demonstrated that astrocyte-specific IL-23 secretion in the GF-IL23 model leads to spontaneous formation of infiltrates after approximately 6 months, especially in the cerebellum with a high proportion of B cells (Nitsch et al, 2019). To further investigate the impact of CNS-specific IL-23-expression on neuroinflammation, we studied the GF-IL23 model using a 2D2 background.…”

Section: Discussionmentioning

confidence: 99%

“…Routine histology and immunohistochemistry of symptomatic GF23-2D2 (age 2.5 months) and age-matched 2D2/ GF-IL23/WT controls (at least n = 6 per genotype) were performed as described previously (Nitsch et al, 2019(Nitsch et al, , 2021. Infiltration of the cerebellum was measured on cross-sections of H&E stains with a semiquantitative score reaching from 0 to 3 points (0 = no infiltration, 3 = highly infiltrated tissue).…”

Section: Routine Histology and Immunohistochemistrymentioning

confidence: 99%

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MOG-Specific T Cells Lead to Spontaneous EAE with Multilocular B Cell Infiltration in the GF-IL23 Model

et al. 2022

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Although IL-23 and downstream signal transduction play essential roles in neuroinflammation, the local impact of IL-23 in multiple sclerosis is still not fully understood. Our previous study revealed that the central nervous system (CNS)-restricted expression of IL-23 in a mouse model with astrocyte-specific expression of IL-23, called GF-IL23 mice, leads to spontaneous formation of infiltrates in the brain, especially in the cerebellum. To further investigate the impact of CNS-specific IL-23-expression on neuroinflammation, we studied the GF-IL23 model in mice expressing a myelin oligodendrocyte glycoprotein (MOG)-specific T cell receptor (GF23-2D2 mice). The GF23-2D2 mice developed a chronic progressive experimental autoimmune encephalomyelitis with myelitis and ataxia without requiring additional immunization. CNS-production of IL-23 alone induced pronounced neuroinflammation in the transgenic MOG-specific T cell receptor model. The GF23-2D2 mice spontaneously developed multilocular infiltrates with a high number of B cells, demyelination and a proinflammatory cytokine milieu indicating that the interaction of encephalitogenic T cells and B cells via co-stimulatory factors seemed to be crucial.

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Section: Discussionmentioning

confidence: 99%

Section: Routine Histology and Immunohistochemistrymentioning

confidence: 99%

MOG-Specific T Cells Lead to Spontaneous EAE with Multilocular B Cell Infiltration in the GF-IL23 Model

et al. 2022

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“…A variety of cells in the central nervous system (CNS) produce IL-17 under physiological conditions, while IL-17R is expressed by immune cells and glial cell populations (112). IL-23 is produced by CNS cells and is a principal mediator of microglial activation, neuroinflammation, and tissue damage (113). There are two ways in which Th17 cells are involved in neuroinflammation, either directly via the production of cytokines (IL-17, IL-21; IL-22; IFN-γ; and G-CSF) or indirectly via the stimulation of neutrophil infiltration and microglial cells, which secrete cytokines, and by attracting CD8+ and Th1 cells to the CNS (114).…”

Section: Discussionmentioning

confidence: 99%

The interleukin-6/interleukin-23/Thelper-17-axis as a driver of neuro-immune toxicity in the major neurocognitive psychosis or deficit schizophrenia: a precision nomothetic psychiatry analysis

Al‐Hakeim

Alhusseini

Al-Dujaili

et al. 2022

Preprint

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Schizophrenia and especially defcit schizophrenia (DSCZ)) are characterized by highly significantly increased activities of neuroimmunotoxic pathways and a generalized cognitive decline (G-CoDe). There are no data whether the interleukin(IL)-6/IL-23/Thelper-17 (IL6/IL23/Th17)-axis is more associated with DSCZ than with non-deficit schizophrenia (NDSCZ) and whether changes in this axis are associated with the G-CoDe and the phenome (a factor extracted from all symptom domains) of schizophrenia. This study included 45 DSCZ and 45 NDSCZ patients and 40 controls and delineated whether the IL6/IL23/Th17 axis, trace elements (copper, zinc) and ions (magnesium, calcium) are associated with DSCZ, the G-CoDe and phenome of schizophrenia. Increased plasma IL-23 and IL-6 levels were associated with Th17 upregulation, assessed as a latent vector (LV) extracted from IL-17, IL-21, IL-22, and TNF-α. The IL6/IL23/Th17-axis score, as assessed by a LV extracted from IL-23, IL-6, and the Th17 LV, was significantly higher in DSCZ than in NDSCZ and controls. We discovered that 70.7% of the variance in the phenome was explained by the IL6/IL23/Th17-axis (positively) and the G-CoDe and IL-10 (both inversely); and that 54.6% of the variance in the G-CoDe was explained by the IL6/IL23/Th17 scores (inversely) and magnesium, copper, calcium, and zinc (all positively). In conclusion, the pathogenic IL6/IL23/Th17-axis contributes to the generalized neurocognitive deficit and the phenome of schizophrenia and especially that of DSCZ due to its key role in peripheral inflammation and neuroinflammation and its consequent immunotoxic effects on neuronal circuits. These clinical impairments are more prominent in subjects with lowered IL-10, magnesium, calcium, and zinc.

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“…Consistent with our observation, Li et al [9] in their research proved that CBX could attenuate clinical score of EAE mice by hindering the differentiation of Th17 cells through inhibiting the secretion of IL-23. It is well-founded that involvement of IL-23 stepped in the inflammatory process of EAE, especially in the accumulation of inflammatory cells and cytokines in CNS [17]. CBX distinctively suppressed EAE pathology through the inhibition of IL-23-related pathways.…”

Section: Discussionmentioning

confidence: 99%

The Effects of Carbenoxolone against Experimental Autoimmune Encephalomyelitis in a Mouse Model

Chen¹,

Hu²,

Li³

et al. 2020

Neuroimmunomodulation

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Introduction: Multiple sclerosis (MS) is a complex demyelinating disease involving central nervous system (CNS). It is still a challenge to secure an effective therapeutic strategy against this disease. Carbenoxolone (CBX) is a derivative of glycyrrhetinic acid, which is widely used in brain research for its gap-junction inhibition effects. Many researchers have observed CBX-mediated suppression of CNS inflammation in their studies. Objective: We want to further examine its anti-inflammation effects in CNS demyelinating disease like MS. Methods: Thus, our study applied an experimental autoimmune encephalomyelitis (EAE) mouse model and examined the effects of CBX on it. Results and Conclusions: We found that CBX significantly reversed the EAE severity and pathology in EAE. IL-17-secreting and IFN-γ-secreting CD4+ T lymphocytes were remarkably lower in the spleen of CBXtreated mice. Production of IL-23 and IL-17 from cortex in EAE animals was markedly reduced by CBX. Furthermore, CBX treatment increased the expression of brain-derived neurotrophic factor. This study provides evidence for the protective role of CBX against EAE.

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CNS-Specific Synthesis of Interleukin 23 Induces a Progressive Cerebellar Ataxia and the Accumulation of Both T and B Cells in the Brain: Characterization of a Novel Transgenic Mouse Model

Cited by 19 publications

References 66 publications

MOG-Specific T Cells Lead to Spontaneous EAE with Multilocular B Cell Infiltration in the GF-IL23 Model

MOG-Specific T Cells Lead to Spontaneous EAE with Multilocular B Cell Infiltration in the GF-IL23 Model

The interleukin-6/interleukin-23/Thelper-17-axis as a driver of neuro-immune toxicity in the major neurocognitive psychosis or deficit schizophrenia: a precision nomothetic psychiatry analysis

The Effects of Carbenoxolone against Experimental Autoimmune Encephalomyelitis in a Mouse Model

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