In vivo nanoparticle imaging of innate immune cells can serve as a marker of disease severity in a model of multiple sclerosis

Abstract

Innate immune cells play a key role in the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis (EAE). Current clinical imaging is restricted to visualizing secondary effects of inflammation, such as gliosis and blood-brain barrier disruption. Advanced molecular imaging, such as iron oxide nanoparticle imaging, can allow direct imaging of cellular and molecular activity, but the exact cell types that phagocytose nanoparticles in vivo and how phagocytic activity relates to disease severity is not well understood. In this study we used MRI to map inflammatory infiltrates using high-field MRI and fluorescently labeled cross-linked iron oxide nanoparticles for cell tracking. We confirmed nanoparticle uptake and MR detectability ex vivo. Using in vivo MRI, we identified extensive nanoparticle signal in the cerebellar white matter and circumscribed cortical gray matter lesions that developed during the disease course (4.6-fold increase of nanoparticle accumulation in EAE compared with healthy controls, P < 0.001). Nanoparticles showed good cellular specificity for innate immune cells in vivo, labeling activated microglia, infiltrating macrophages, and neutrophils, whereas there was only sparse uptake by adaptive immune cells. Importantly, nanoparticle signal correlated better with clinical disease than conventional gadolinium (Gd) imaging (r, 0.83 for nanoparticles vs. 0.71 for Gd-imaging, P < 0.001). We validated our approach using the Food and Drug Administration-approved iron oxide nanoparticle ferumoxytol. Our results show that noninvasive molecular imaging of innate immune responses can serve as an imaging biomarker of disease activity in autoimmune-mediated neuroinflammation with potential clinical applications in a wide range of inflammatory diseases.MRI | nanoparticle imaging | USPIO | multiple sclerosis | EAE

Wide-field dynamic monitoring of immune cell trafficking in murine models of glioblastoma

“…Efficient phagocytosis can be co-opted to densely label leukocytes with nanoparticles in cell cultures and in live animal tissues following systemic particle administration for the study of various diseases. 4,6,9,11,35 Our results suggest a similar fate for intravenously-injected LGNRs. The absence of…”

Microglial Phenotypes and Functions in Multiple Sclerosis

“…It has more recently been complemented by the use of ultrasmall iron particles (USPIOs), which are taken up by macrophages in the circulation or by microglia in conditions of blood-brain barrier (BBB) damage and allow tracing of these cells in vivo using iron-sensitive MRI sequences. A recent study by Kirschbaum et al (2016), using MRI and nanoparticles to determine pathology in EAE, showed that the majority of myeloid effector cells have the ability to phagocytose nanoparticles, including microglia, macrophages, and neutrophils, which is a unique approach to imaging the inflammatory responses in EAE. In addition, they used ferumoxytol (Food and Drug Administration [FDA] approved) iron oxide nanoparticles to show that labeled activated microglia, infiltrating macrophages, and neutrophils can be imaged across disease progression in EAE.…”

Gliosis and Neurodegenerative Diseases: The Role of PET and MR Imaging

“…Among novel imaging tools, different nanoparticles (usually smaller than 100 nm) have been extensively used in preclinical settings as MRI contrast agent combined with a PET tracer, mainly for oncological and more recently cardiovascular imaging (Aime et al, 2002;Uppal et al, 2011;Lewis et al, 2015;Kirschbaum et al, 2016;Vecchione et al, 2017;Grimaldi et al, 2019). Recently, a potential multimodal PET/MRI probe has been described to target microglia and neuroinflammation in a mouse model (Tang et al, 2018).…”