期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：46
页码：13227-13232
DOI：10.1073/pnas.1609397113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceMultiple sclerosis is a devastating neurological condition that can affect the entire central nervous system. Innate immune cells mediate the underlying tissue damage, but visualizing these cellular culprits is currently not possible. Diagnosis and treatment monitoring are performed by MRI, but so far imaging markers are unspecific and based on secondary parameters (edema/gliosis; blood-brain barrier disruption). We used a nanoparticle-based approach to image brain-resident and infiltrating innate immune cells in inflammatory lesions. Nanoparticle uptake is specific for innate immune cells and correlates with clinical severity. Thus, targeting innate immunity by molecular imaging may serve as a direct marker of disease activity with the potential of clinical translation to a wide variety of inflammatory conditions for improved diagnosis and treatment monitoring. 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.
