Abstract
Monocytes are circulating macrophage and dendritic cell precursors that populate healthy and diseased tissue. In humans, monocytes consist of at least two subsets whose proportions in the blood fluctuate in response to coronary artery disease, sepsis, and viral infection. Animal studies have shown that specific shifts in the monocyte subset repertoire either exacerbate or attenuate disease, suggesting a role for monocyte subsets as biomarkers and therapeutic targets. Assays are therefore needed that can selectively and rapidly enumerate monocytes and their subsets. This study shows that two major human monocyte subsets express similar levels of the receptor for macrophage colony stimulating factor (MCSFR) but differ in their phagocytic capacity. We exploit these properties and custom-engineer magnetic nanoparticles for ex vivo sensing of monocytes and their subsets. We present a two-dimensional enumerative mathematical model that simultaneously reports number and proportion of monocyte subsets in a small volume of human blood. Using a recently described diagnostic magnetic resonance (DMR) chip with 1 µl sample size and high throughput capabilities, we then show that application of the model accurately quantifies subset fluctuations that occur in patients with atherosclerosis.
Highlights
Circulating monocytes in humans fall into subsets typically identified by expression of the LPS receptor CD14 and the Fcc receptor-III CD16
Neutrophils, which were absent in the preparations, express markers such as CD14, CD16, CD11b and MPO, but not macrophage colony stimulating factor (MCSFR)
Freshly-isolated monocyte subsets phagocytose fluorescently-labeled latex beads differently: both subsets are positive for bead uptake, but the cellular bead concentration, as assessed by the beads’ mean fluorescent intensity (MFI), is significantly higher in the CD16lo population, indicating higher phagocytosis by this subset compared to its CD16hi counterpart (Fig. 1E)
Summary
Circulating monocytes in humans fall into subsets typically identified by expression of the LPS receptor CD14 and the Fcc receptor-III CD16. CD14+CD16lo monocytes predominate in the blood and express high levels of the CCL2 (MCP-1) receptor CCR2 while CD14loCD16hi monocytes are less abundant and express higher levels of the fractalkine receptor CX3CR1. These expression patterns suggest differential tissue tropism, and indicate commitment of circulating monocytes for specific functional fates [1,2,3,4]. Recent studies in animals have promoted the idea, that some monocyte subsets accentuate while others attenuate disease [8]. In this context, disease progression may be characterized by a subset imbalance that favors an inflammatory cell population. The possibility that monocytes participate divergently in lesion growth necessitates evaluation of how findings obtained in animals translate to humans, and whether monocyte subsets represent therapeutic targets and prognostic biomarkers
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