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.

Interleukin 23 (IL-23) is a key mediator in neuroinflammation in numerous autoimmune diseases including multiple sclerosis (MS). However, the pathophysiology of IL-23 and how it contributes to neuroinflammation is poorly defined. To further clarify the role of IL-23 in CNS inflammation, we generated a transgenic mouse model (GF-IL23) with astrocyte-targeted expression of both IL-23 subunits, IL-23p19, and IL-23p40. These GF-IL23 mice spontaneously develop a progressive ataxic phenotype, which corresponds to cerebellar tissue destruction, and inflammatory infiltrates most prominent in the subarachnoidal and perivascular space. The CNS-cytokine milieu was characterized by numerous inflammatory mediators such as IL-17a and IFNγ. However, the leukocytic infiltrates were surprisingly predominated by B cells. To further examine the impact of the CNS-specific IL-23 synthesis on an additional systemic inflammatory stimulus, we applied the LPS-induced endotoxemia model. Administration of LPS in GF-IL23 mice resulted in early and pronounced microglial activation, enhanced cytokine production and, in sharp contrast to control animals, in the formation of lymphocytic infiltrates. Our model confirms a critical role for IL-23 in the induction of inflammation in the CNS, in particular facilitating the accumulation of lymphocytes in and around the brain. Thereby, CNS-specific synthesis of IL-23 is able to induce a cascade of inflammatory cytokines leading to microglia activation, astrocytosis, and ultimately tissue damage. The presented transgenic model will be a useful tool to further dissect the role of IL-23 in neuroinflammation.

Astroglial NF-kB contributes to white matter damage and cognitive impairment in a mouse model of vascular dementia.

Vascular cognitive impairment is the second most common form of dementia. The pathogenic pathways leading to vascular cognitive impairment remain unclear but clinical and experimental data have shown that chronic reactive astrogliosis occurs within white matter lesions, indicating that a sustained pro-inflammatory environment affecting the white matter may contribute towards disease progression. To model vascular cognitive impairment, we induced prolonged mild cerebral hypoperfusion in mice by bilateral common carotid artery stenosis. This chronic hypoperfusion resulted in reactive gliosis of astrocytes and microglia within white matter tracts, demyelination and axonal degeneration, consecutive spatial memory deficits, and loss of white matter integrity, as measured by ultra high-field magnetic resonance diffusion tensor imaging. White matter astrogliosis was accompanied by activation of the pro-inflammatory transcription factor nuclear factor (NF)-kB in reactive astrocytes. Using mice expressing a dominant negative inhibitor of NF-kB under the control of the astrocyte-specific glial fibrillary acid protein (GFAP) promoter (GFAP-IkBα-dn), we found that transgenic inhibition of astroglial NF-kB signaling ameliorated gliosis and axonal loss, maintained white matter structural integrity, and preserved memory function. Collectively, our results imply that pro-inflammatory changes in white matter astrocytes may represent an important detrimental component in the pathogenesis of vascular cognitive impairment, and that targeting these pathways may lead to novel therapeutic strategies.

Erratum to: Interleukin-1beta-induced reduction of tissue water diffusion in the juvenile rat brain on ADC MRI is not associated with (31)P MRS-detectable energy failure.

[This corrects the article DOI: 10.1186/s12950-016-0118-3.].

Interleukin-1beta-induced reduction of tissue water diffusion in the juvenile rat brain on ADC MRI is not associated with (31)P MRS-detectable energy failure.

BACKGROUND: It has long been known that an intrastriatal microinjection of the archetypal pro-inflammatory cytokine, interleukin-1beta (IL-1ß), in juvenile rats induces a chronic reduction in the apparent diffusion coefficient (ADC) of tissue water on magnetic resonance imaging (MRI). Reduced ADC during acute cerebral ischaemia is an established indicator of metabolic failure whereas the cause of the IL-1ß-induced reduction remains to be deciphered. Previously, it has been shown that IL-1ß does not perturb the phosphorus ((31)P) magnetic resonance spectroscopy (MRS)-detectable energy status of an ex vivo preparation of rat brain parenchyma that is devoid of a functional vasculature component. However, brain energy status following an IL-1ß challenge in vivo remains to be examined. METHODS: This study is the first longitudinal in vivo examination of the correlation of ADC MRI with localised (31)P MRS signals obtained specifically from within the injected and non-injected striatum following IL-1ß (1 ng/ul or 100 ng/ul) challenge, in real-time. RESULTS: Despite observing a chronic reduction in ADC at either dose of IL-1ß challenge, energy compromise was not detected at any time point. CONCLUSIONS: The IL-1ß-induced effects pertaining to a functional vasculature such as leukocyte recruitment, blood-brain barrier (BBB) breakdown and blood flow changes are unlikely to impact on overall tissue energy status. Compared to classic ischaemia, there is dissociation between ADC and energy status within an IL-1ß-induced lesion in vivo.

Characterisation of endothelin-1-induced intrastriatal lesions within the juvenile and adult rat brain using MRI and 31P MRS.

Improved non-invasive magnetic resonance (MR) characterisation of in vivo models of focal ischaemic insults such as transient ischaemic attack (TIA) and perinatal arterial ischaemic stroke (AIS) may assist diagnosis, outcome prediction and treatment design. The classic middle cerebral artery occlusion (MCAO) model of ischaemic stroke is well documented in MR studies but generates extensive and complex lesions involving an acute inflammatory response and de-occlusion that immediately restores circulation. By contrast, intrastriatal microinjection of the potent vasoconstrictor, endothelin-1 (ET-1), induces a focal, reversible and low-flow ischaemia in the absence of a typical inflammatory response, which gradually restores blood flow over several hours and may be more relevant to TIA and AIS pathology. This study presents the first comprehensive longitudinal MR characterisation of the real-time anatomical [T1-weighted (T1-w)/T2-weighted (T2-w)], pathophysiological [apparent diffusion coefficient (ADC), cerebral blood volume, gadolinium contrast imaging of blood-brain barrier (BBB) integrity] and metabolic [phosphorus magnetic resonance spectroscopy (31P MRS)] evolution of a purely ischaemic ET-1-induced lesion within the juvenile and adult rat brain. ET-1-induced cytotoxic oedema was visualised on T2-w magnetic resonance imaging (MRI), inconsistent with the conventional notion that it cannot be detected using anatomical MRI. There was no immunohistochemical evidence of an acute inflammatory response or loss of BBB integrity, thus excluding a vasogenic oedema contribution to the pathology. Maximal T2-w intensity correlated with the lowest ADC value in both age groups, re-emphasising the purely ischaemic nature of the lesion and the absence of vasogenic oedema. Furthermore, extensive acute T1-w hypointensity was observed in the presence of cytotoxic oedema-induced T2-w changes, whereas other authors have shown that increased T1 values following MCAO reflect vasogenic oedema. Intriguingly, the lesion border exhibited hyperintensity on T2-w and ADC MRI at later time points, and the former may be a consequence of phagocytosis-induced fatty droplet deposition by macrophages detected immunohistochemically. In spite of a chronically reduced ADC, typically associated with ischaemia-induced energy failure, a 31P MRS-detectable reduction in the phosphocreatine (PCr) to gamma adenosine triphosphate (γATP) ratio was not observed at any time point in either age group, suggesting dissociation of tissue water diffusion and metabolic changes within the ET-1-induced lesion.

Interleukin-1beta does not affect the energy metabolism of rat organotypic hippocampal-slice cultures.

The aim of this study was to examine the effect of the archetypal pro-inflammatory cytokine, interleukin-1beta (IL-1ß), on high-energy phosphate levels within an ex vivo rat organotypic hippocampal-slice culture (OHSC) preparation using phosphorus ((31)P) magnetic resonance spectroscopy (MRS). Intrastriatal microinjection of IL-1ß induces a chronic reduction in the apparent diffusion coefficient (ADC) of tissue water, which may be indicative of metabolic failure as established by in vivo models of acute cerebral ischaemia. The OHSC preparation enables examination of the effects of IL-1ß on brain parenchyma per se, independent of the potentially confounding effects encountered in vivo such as perfusion changes, blood-brain barrier (BBB) breakdown and leukocyte recruitment. (31)P MRS is a technique that can detect multiple high-energy phosphate metabolites within a sample non-invasively. Here, for the first time, we characterise the energy metabolism of OHSCs using (31)P MRS and demonstrate that IL-1ß does not compromise high-energy phosphate metabolism. Thus, the chronic reduction in ADC observed in vivo is unlikely to be a consequence of metabolic failure.

In the eye of experimental cerebral malaria.

Cerebral malaria is the most severe complication of Plasmodium falciparum infection, accounting for 1 million deaths per year. We characterized the murine disease using in vivo magnetic resonance imaging (MRI) at 4.7 T, proving that ischemic edema is responsible for fatality. The aim of the present study was to identify early markers of experimental cerebral malaria using very high field conventional MRI (11.75 T). CBA/J mice infected with Plasmodium berghei ANKA were observed at an early stage of the disease, before the onset of detectable brain swelling and at the most acute stage of cerebral malaria. Herein, we report the first detection of damage to the optic and trigeminal nerves on T(2)-weighted MRI. The trigeminal nerves appeared hypointense, with significantly reduced diameter and cross-sectional area. The optic nerves were hypointense and often not visible. In addition, the internerve distance between the optic nerves was significantly and progressively reduced between the early and severest stages. Cranial nerve injury was the earliest anatomic hallmark of the disease, visible before brain edema became detectable. Thus, cranial nerve damage may manifest in neurologic signs, which may assist in the early recognition of cerebral malaria.