Non-invasive mapping of systemic neutrophil dynamics upon cardiovascular injury

Abstract

Neutrophils play a complex role during onset of tissue injury and subsequent resolution and healing. To assess neutrophil dynamics upon cardiovascular injury, here we develop a non-invasive, background-free approach for specific mapping of neutrophil dynamics by whole-body magnetic resonance imaging using targeted multimodal fluorine-loaded nanotracers engineered with binding peptides specifically directed against murine or human neutrophils. Intravenous tracer application before injury allowed non-invasive three-dimensional visualization of neutrophils within their different hematopoietic niches over the entire body and subsequent monitoring of their egress into affected tissues. Stimulated murine and human neutrophils exhibited enhanced labeling due to upregulation of their target receptors, which could be exploited as an in vivo readout for their activation state in both sterile and nonsterile cardiovascular inflammation. This non-invasive approach will allow us to identify hidden origins of bacterial or sterile inflammation in patients and also to unravel cardiovascular disease states on the verge of severe aggravation due to enhanced neutrophil infiltration or activation.

Cross-Modal Imaging Reveals Nanoparticle Uptake Dynamics in Hematopoietic Bone Marrow during Inflammation

“…This finding was documented through both in vivo R2* mapping and fluorescent IVIS imaging techniques. While at first this may appear contradictoryconsidering that inflammation typically prompts a release of innate immune cells from the bone marrow , this phenomenon is in fact consistent with the established dynamics of iron recirculation to the erythroid marrow. The uptake of nanoparticles at the bone marrow under normal circumstances has been described in other studies employing iron oxide nanoparticle-enhanced imaging. ,, This enhanced bone marrow uptake during inflammation is actually in alignment with the recognized patterns of iron distribution, which include the recycling of iron back to the erythroid marrow where red blood cells are formeda process that is part of the body’s normal response to inflammation .…”

“…This finding was documented through both in vivo R2* mapping and fluorescent IVIS imaging techniques. While at first this may appear contradictory—considering that inflammation typically prompts a release of innate immune cells from the bone marrow 9 , 34 —this phenomenon is in fact consistent with the established dynamics of iron recirculation to the erythroid marrow. The uptake of nanoparticles at the bone marrow under normal circumstances has been described in other studies employing iron oxide nanoparticle-enhanced imaging.…”

Perfluorocarbons: A perspective of theranostic applications and challenges

“…Bouvain and colleagues generate a noninvasive approach for explicit mapping of neutrophil dynamics by 19F-based MRI probes, using PFCs. In-vivo data showed this technique let to recognize undercover origins of inflammation in patients and also to separate cardiovascular disease circumstances on the point of extreme aggravation due to enriched neutrophil infiltration or activation (Bouvain et al, 2023). Liposomal bubbles (bubble liposome, BL) constructed of PFC gas and nano-sized liposomes covered by RGD sequence peptides on their exterior shell.…”

Cardiovascular Molecular Imaging With Fluorine-19 MRI: The Road to the Clinic

“…Since 19 F MRI holds the potential to characterize the role of distinct leukocyte populations, it could yield spatial information on the contribution of different immune cell subsets to reperfusion injury in the directly affected myocardium and along the infarct border zone. Using (multi)-targeted approaches, 11 even bone marrow activation and the entire development cascade from atherosclerosis to AMI 12 can be tracked. Immune-cell-specific 19 F MRI approaches further harbor the potential for identification and treatment guidance 13 of patients with stable coronary artery disease, but plaque-derived inflammation, 14 which are at risk of future complications (AMI, stroke).…”

“…Targeted PFCs can likewise be engineered with antibodies or binding peptides specifically directed against integrins expressed in angiogenesis 54 or cell populations such as neutrophils. 11 In the latter study, intravenous tracer injection prior to ischemia-reperfusion injury allowed the noninvasive 3D visualization of neutrophils within their different hematopoietic niches throughout the body and the subsequent monitoring of their egress into myocardium due the myocardial injury (Figure 6).…”