Detection of Monocyte/Macrophage and Microglia Activation in the TMEV Model of Chronic Demyelination Using USPIO‐Enhanced Ultrahigh‐Field Imaging

Abstract

BACKGROUND AND PURPOSE: Blood-derived monocytes/macrophages can be labeled with ultrasmall superparamagnetic iron oxides (USPIO) at periphery and subsequently migrate into areas of inflammation in the brain. We investigated temporal pattern of migration of peripheral immune cells in Theiler's murine encephalomyelitis virus (TMEV) model of chronic demyelination by USPIO-enhanced imaging. METHODS: Fifteen SJL mice (Envigo, Indianapolis, IN) were injected with TMEV (n = 12) or saline (n = 3) at 7 weeks of age. Brain MRI of 9.4 T was performed at 3 months postinfection (mpi) (the peak of inflammatory phase), at 4, 5, and 7 mpi (throughout neurodegenerative phase) using T2*-weighted gradient echo MRI, and performed 24 hours after USPIO injection. Contrast enhancing lesion (CEL) number and volume were measured and development of brain atrophy was assessed across serial time points. Clinical disability scale and rotarod score assessed disease progression. RESULTS: CEL was detected in a total of eight (66.7%) TMEV-infected animals and none of the Controls. The CEL was present in four (33.3%) TMEV-infected animals at 3 mpi, two (16.7%) at 4 mpi, six (54.5%) at 5 mpi, and four (44.4%) at 7 mpi, respectively. In TMEV-infected animals, the CEL number and volume increased significantly from 3 to 7 mpi (P < .01 for both). The correlation between total CEL number and volume with clinical and MRI outcomes was trending (P < .05). On histopathology analysis, CEL showed increased density of Iba1 staining for microglia activity. CONCLUSIONS: Serial USPIO imaging is a promising biomarker for investigating the effect of therapeutic interventions on monocytes/macrophages and microglia activation and neurodegeneration in TMEV-infected animals.

Magnetic resonance imaging approaches for studying mouse models of multiple sclerosis: A mini review

“…This cellular activation, confirmed by Iba1 immunohistochemistry staining, showed a trending correlation with clinical and MRI outcomes (Zivadinov et al, 2020).…”

“…The study focused on monocyte/macrophage and microglial cells, showing an increasing activation of these cells from 3 to 7 months post‐infection. This cellular activation, confirmed by Iba1 immunohistochemistry staining, showed a trending correlation with clinical and MRI outcomes (Zivadinov et al, 2020).…”

“…Authors have used a TMEV‐IDD not susceptible mouse strain, that is, C57BL/6 mice and IFNγ receptor knock‐out mice, to induce a more severe and acute disease (Pirko, Johnson et al, 2004; Pirko, Gamez et al, 2004). Conversely, a more recent study has investigated the temporal migration pattern of immune cells in the chronic progressive TMEV‐IDD model (Zivadinov et al, 2020). The study focused on monocyte/macrophage and microglial cells, showing an increasing activation of these cells from 3 to 7 months post‐infection.…”

Contribution of Intravital Neuroimaging to Study Animal Models of Multiple Sclerosis

“…Many iron-rich areas can thus be highlighted in macrophageenriched demyelinated lesions named contrast enhancing lesion (CEL). Their number is specifically high between the onset and the peak of EAE disease as well as during the progressive phase of the TMEV mouse model [108,109].…”

Protective Effect of Bruton Tyrosine Kinase Inhibitor in Murine Model of Chronic Demyelination

“…[14,15] During the TMEV disease course, the microglia are capable antigen-presenting cells that play an important role at the onset of clinical disease and contribute to demyelination. [16,17] Furthermore, B cell activation and secretion of auto antibodies has been shown to participate in the TMEV disease pathology as well. [18] Therefore, in comparison to a T cell driven immunization based preclinical Experimental autoimmune encephalomyelitis (EAE) disease model, TMEV is better suited for characterizing iBTK's role in MS disease pathology.…”