A mathematical model for the role of macrophage chemotactic emigration in the early atherosclerotic plaque

TL;DR

This paper introduces a spatial mathematical model to understand how macrophage chemotactic emigration influences early atherosclerotic plaque development, highlighting the role of internal elastic lamina and chemotactic signal range.

Contribution

The study develops a novel spatial model combining mathematical analysis and simulations to explore macrophage emigration mechanisms in early plaque formation.

Findings

Macrophage transit times predict long-term lipid burden.

Internal elastic lamina can limit macrophage emigration rate.

Short-range chemoattractant signals may increase macrophage emigration.

Abstract

Atherosclerotic plaques are fatty, cellular lesions that form in artery walls. The early plaque contains monocyte-derived macrophages, which are recruited to consume locally bound lipid deposits. Plaque progression is characterised by an imbalance in the rates of cell entry and exit from the plaque, which can occur if macrophages die in situ rather than leave by emigration. The mechanisms that regulate macrophage emigration are not well understood, but there is evidence that a chemotactic response can guide macrophages out of the plaque towards the artery wall lymphatics. In this paper, we develop a novel spatial model of the early plaque to study the implications of macrophage chemotactic emigration. Using mathematical analysis and numerical simulations, we investigate how the properties of the chemotactic response contribute to the spatial characteristics and lipid burden of the model plaque. Calculations of macrophage transit times are found to provide a reliable indicator of long-term plaque lipid burden, and also highlight the potential rate-limiting effect of the internal elastic lamina (IEL) on chemotactic emigration. When macrophage emigration is rate-limited by the IEL, we observe non-monotonic cell and lipid profiles that are associated with macrophage accumulation deep in the plaque. The model further predicts that when the chemoattractant penetrates only a short distance into the plaque, the proportion of emigrating macrophages may increase relative to that for a longer-range signal. The theoretical observations in this study can potentially be used to identify evidence of macrophage emigration in data from real atherosclerotic plaques.