Abstract
In neuroinflammatory disorders such as multiple sclerosis, the physiological function of the blood-brain barrier (BBB) is perturbed, particularly in demyelinating lesions and supposedly secondary to acute demyelinating pathology. Using the toxic non-inflammatory cuprizone model of demyelination, we demonstrate, however, that the onset of persistent BBB impairment precedes demyelination. In addition to a direct effect of cuprizone on endothelial cells, a plethora of inflammatory mediators, which are mainly of astroglial origin during the initial disease phase, likely contribute to the destabilization of endothelial barrier function in vivo. Our study reveals that, at different time points of pathology and in different CNS regions, the level of gliosis correlates with the extent of BBB hyperpermeability and edema. Furthermore, in mutant mice with abolished type 3 CXC chemokine receptor (CXCR3) signaling, inflammatory responses are dampened and BBB dysfunction ameliorated. Together, these data have implications for understanding the role of BBB permeability in the pathogenesis of demyelinating disease.
Highlights
The cerebral vasculature controls and restricts the transport of biomolecules between blood and the CNS parenchyma by means of the blood-brain barrier (BBB) [1, 37]
We previously showed in the non-inflammatory cuprizone model of demyelination [45], that BBB permeability is increased at the peak of demyelinating disease, and that this BBB dysfunction can be utilized for CNS delivery of therapeutics [11]
When we quantified the levels of inflammatory mediators that have previously been shown to induce BBB dysfunction [42, 47, 58], Tnf, Il1b, and Ccl2 (C-C Motif Chemokine Ligand 2) were strongly upregulated (Fig. 1b)
Summary
The cerebral vasculature controls and restricts the transport of biomolecules between blood and the CNS parenchyma by means of the blood-brain barrier (BBB) [1, 37]. In a wide range of neurological disorders including multiple sclerosis (MS) increased vascular permeability has been observed [33] but the primary cause for the pathophysiology of the NVU and the relation to disease specific pathomechanisms remains unclear. We previously showed in the non-inflammatory cuprizone model of demyelination [45], that BBB permeability is increased at the peak of demyelinating disease, and that this BBB dysfunction can be utilized for CNS delivery of therapeutics [11]. It is unclear which pathomechanism triggers the BBB breach in the cuprizone model. We demonstrate that early disease processes are associated with elevated levels of several pro-inflammatory mediators of predominantly astroglial
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