There is a broad consensus that multiple sclerosis (MS) represents more than an inflammatory disease: it harbors several characteristic aspects of a classical neurodegenerative disorder, that is, damage to axons, synapses and nerve cell bodies. While we are equipped with appropriate therapeutic options to prevent immune-cell driven relapses, effective therapeutic options to prevent the progressing neurodegeneration are still missing. In this review article, we will discuss to what extent pathology of the progressive disease stage can be modeled in MS animal models. While acute and relapsing-remitting forms of experimental autoimmune encephalomyelitis (EAE), which are T cell dependent, are aptly suited to model relapsing-remitting phases of MS, other EAE models, especially the secondary progressive EAE stage in Biozzi ABH mice is better representing the secondary progressive phase of MS, which is refractory to many immune therapies. Besides EAE, the cuprizone model is rapidly gaining popularity to study the formation and progression of demyelinating CNS lesions without T cell involvement. Here, we discuss these two non-popular MS models. It is our aim to point out the pathological hallmarks of MS, and discuss which pathological aspects of the disease can be best studied in the various animal models available.

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.

Key Points• ADAM10 but not ADAM17 on leukocytes is essential for chemokine-induced signaling, adhesion, cytoskeletal rearrangement, and migration.• Leukocyte-expressed ADAM10 promotes leukocyte recruitment and edema formation in a murine model of acute pulmonary inflammation.Inflammation is a key process in various diseases, characterized by leukocyte recruitment to the inflammatory site. This study investigates the role of a disintegrin and a metalloproteinase (ADAM) 10 and ADAM17 for leukocyte migration in vitro and in a murine model of acute pulmonary inflammation. Inhibition experiments or RNA knockdown indicated that monocytic THP-1 cells and primary human neutrophils require ADAM10 but not ADAM17 for efficient chemokine-induced cell migration. Signaling and adhesion events that are linked to cell migration such as p38 and r GTPase-family activation, F-actin polymerization, adhesion to fibronectin, and upregulation of a 5 integrin were also dependent on ADAM10 but not ADAM17. This was confirmed with leukocytes isolated from mice lacking either ADAM10 or ADAM17 in all hematopoietic cells (vav 1 guanine nucleotide exchange factor [Vav]-Adam10 2/2 or Vav-Adam17 2/2 mice). In lipopolysaccharide-induced acute pulmonary inflammation, alveolar recruitment of neutrophils and monocytes was transiently increased in Vav-Adam17 2/2 but steadily reduced in Vav-Adam10 2/2 mice. This deficit in alveolar leukocyte recruitment was also observed in LysM-Adam10 2/2 mice lacking ADAM10in myeloid cells and correlated with protection against edema formation. Thus, with regard to leukocyte migration, leukocyteexpressed ADAM10 but not ADAM17 displays proinflammatory activities and may therefore serve as a target to limit inflammatory cell recruitment. (Blood. 2014;123(26):4077-4088)

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