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Nanoparticle immunoimaging reveals metabolic dysfunction fueling CCR2-dependent inflammation in infarcted hearts

Year: 2025

Type: article

Abstract: Inflammation critically shapes outcomes after myocardial infarction (MI), particularly in patients with metabolic dysfunction. This study investigated the uptake of fluorescent cross-linked iron oxide nanoparticles (CLIO-AF647) in infarcted myocardium and hematopoietic bone marrow using multimodal imaging, with emphasis on the role of metabolic stress and CCR2 signaling. Male C57BL/6 J mice underwent MI with or without diet-induced obesity (DIO) established by a high-fat, high-glucose diet. CLIO-AF647 was injected intravenously two days post-MI. Myocardial uptake was assessed by magnetic resonance imaging (MRI, T2* mapping) at days 2 and 4, complemented by optical imaging/computed tomography (OI/CT), flow cytometry, and histology. CCR2 inhibition (RS102895, 2 mg/kg IP) was applied from day 0–4, and cardiac function was monitored until day 21. DIO mice showed significantly increased CLIO-AF647 uptake in infarcted myocardium and femoral bone marrow compared with controls. CCR2 blockade reduced nanoparticle accumulation in both tissues, confirming specificity for CCR2 + myeloid cells. Flow cytometry demonstrated nanoparticle uptake by inflammatory Ly6C high and reparative Ly6C int/low monocytes, as well as neutrophils, in blood and infarcted tissue. In vitro, lineage − hematopoietic progenitors cultured under high glucose and lipopolysaccharide stimulation exhibited enhanced nanoparticle uptake, supporting metabolic and TLR4-driven mechanisms. At 21 days, DIO mice displayed aggravated adverse remodeling, which was attenuated by CCR2 inhibition. Importantly, early ΔT2* values strongly correlated with later cardiac outcomes. These findings establish CLIO-AF647 as a noninvasive imaging tool for CCR2-dependent myeloid cell activity in metabolically stressed MI, offering both a predictive biomarker and preclinical support for CCR2-targeted therapies in cardiovascular disease.

Source: Journal of Controlled Release

DOI: 10.1016/j.jconrel.2025.114399