Combination of cuprizone and experimental autoimmune encephalomyelitis to study inflammatory brain lesion formation and progression

Abstract

Brain-intrinsic degenerative cascades are a proposed factor driving inflammatory lesion formation in multiple sclerosis (MS) patients. We recently described a model combining noninflammatory cytodegeneration (via cuprizone) with the classic active experimental autoimmune encephalomyelitis (Cup/EAE model), which exhibits inflammatory forebrain lesions. Here, we describe the histopathological characteristics and progression of these Cup/EAE lesions. We show that inflammatory lesions develop at various topographical sites in the forebrain, including white matter tracts and cortical and subcortical grey matter areas. The lesions are characterized by focal demyelination, discontinuation of the perivascular glia limitans, focal axonal damage, and neutrophil granulocyte extravasation. Transgenic mice with enhanced green fluorescent protein-expressing microglia and red fluorescent protein-expressing monocytes reveal that both myeloid cell populations contribute to forebrain inflammatory infiltrates. EAE-triggered inflammatory cerebellar lesions were augmented in mice pre-intoxicated with cuprizone. Gene expression studies suggest roles of the chemokines Cxcl10, Ccl2, and Ccl3 in inflammatory lesion formation. Finally, follow-up experiments in Cup/EAE mice with chronic disease revealed that forebrain, but not spinal cord, lesions undergo spontaneous reorganization and repair. This study underpins the significance of brain-intrinsic degenerative cascades for immune cell recruitment and, in consequence, MS lesion formation.

Pathology of inflammatory diseases of the nervous system: Human disease versus animal models

“…Finally, in another study EAE was induced in animals with cuprizone related demyelinating lesions in a timing, which resulted in the appearance of inflammatory lesions at sites of microglia activation, active demyelination, and neurodegeneration in the corpus callosum. Similarly to the previous study, inflammatory lesions were preferentially precipitated to the side of microglia activation and brain damage, but the EAE typical pattern of brain inflammation or the extent of tissue damage was neither altered by the presence of inflammation at the site of microglia activation nor by the presence of microglia preactivation at the site of EAE-induced brain inflammation (Ruther et al, 2017).…”

Animal models of multiple sclerosis: Focus on experimental autoimmune encephalomyelitis

“…Recently, cuprizone was used in combination with actively induced EAE, resulting in inflammatory forebrain lesions (Ruther et al, ; Scheld et al, ). Therefore, this model may be an extremely valuable tool in MS research in the future.…”

Oligodendrocyte degeneration and concomitant microglia activation directs peripheral immune cells into the forebrain

“…Although the accumulation of peripheral immune cells is a characteristic of such lesions, it is not clear what triggers the influx of immune cells into the central nervous system (CNS). However, a degenerative process within the brain has been suggested as one potential trigger mechanism (De Groot, Bergers et al 2001, Barnett and Prineas 2004, Scheld, Ruther et al 2016, Ruther, Scheld et al 2017. Indeed, that damage to the brain parenchyma can trigger the site of inflammatory lesion formation, is well known.…”