Search

Macrophages in atherosclerotic lesions exhibit a spectrum of behaviours or phenotypes. The phenotypic distribution of monocyte-derived macrophages (MDMs), its correlation with MDM lipid content, and relation to blood lipoprotein densities are not well understood. Of particular interest is the balance between low density lipoproteins (LDL) and high density lipoproteins (HDL), which carry bad and good cholesterol respectively. To address these issues, we have developed a mathematical model for early atherosclerosis in which the MDM population is structured by phenotype and lipid content. The model admits a simpler, closed subsystem whose analysis shows how lesion composition becomes more pathological as the blood density of LDL increases relative to the HDL capacity. We use asymptotic analysis to derive a power-law relationship between MDM phenotype and lipid content at steady-state. This relationship enables us to understand why, for example, lipid-laden MDMs have a more inflammatory phenotype than lipid-poor MDMs when blood LDL lipid density greatly exceeds HDL capacity. We show further that the MDM phenotype distribution always attains a local maximum, while the lipid content distribution may be unimodal, adopt a quasi-uniform profile or decrease monotonically. Pathological lesions exhibit a local maximum in both the phenotype and lipid content MDM distributions, with the maximum at an inflammatory phenotype and near the lipid content capacity respectively. These results illustrate how macrophage heterogeneity arises in early atherosclerosis and provide a framework for future model validation through comparison with single-cell RNA sequencing data., (© 2024. The Author(s).)

Atherosclerotic plaques are fatty deposits that form in the walls of major arteries and are one of the major causes of heart attacks and strokes. Macrophages are the main immune cells in plaques and macrophage dynamics influence whether plaques grow or regress. Macrophage proliferation is a key process in atherosclerosis, particularly in the development of mid-stage plaques, but very few mathematical models include proliferation. In this paper we reframe the lipid-structured model of Ford et al. (J Theor Biol 479:48-63, 2019. https://doi.org/10.1016/j.jtbi.2019.07.003 ) to account for macrophage proliferation. Proliferation is modelled as a non-local decrease in the lipid structural variable. Steady state analysis indicates that proliferation assists in reducing eventual necrotic core lipid content and spreads the lipid load of the macrophage population amongst the cells. The contribution of plaque macrophages from proliferation relative to recruitment from the bloodstream is also examined. The model suggests that a more proliferative plaque differs from an equivalent (defined as having the same lipid content and cell numbers) recruitment-dominant plaque in the way lipid is distributed amongst the macrophages. The macrophage lipid distribution of an equivalent proliferation-dominant plaque is less skewed and exhibits a local maximum near the endogenous lipid content., (© 2024. The Author(s).)

Atherosclerotic plaques are fatty growths in artery walls that cause heart attacks and strokes. Plaque formation is driven by macrophages that are recruited to the artery wall. These cells consume and remove blood-derived lipids, such as modified low-density lipoprotein. Ineffective lipid removal, due to macrophage death and other factors, leads to the accumulation of lipid-loaded macrophages and formation of a necrotic lipid core. Experimental observations suggest that macrophage functionality varies with the extent of lipid loading. However, little is known about the influence of macrophage lipid loads on plaque fate. Extending work by Ford et al. (J Theor Biol 479:48-63, 2019) and Chambers et al. (A lipid-structured model of atherosclerosis with macrophage proliferation, 2022), we develop a plaque model where macrophages are structured by their ingested lipid load and behave in a lipid-dependent manner. The model considers several macrophage behaviours, including recruitment to and emigration from the artery wall; proliferation and apotosis; ingestion of plaque lipids; and secondary necrosis of apoptotic cells. We consider apoptosis, emigration and proliferation to be lipid-dependent and we model these effects using experimentally informed functions of the internalised lipid load. Our results demonstrate that lipid-dependent macrophage behaviour can substantially alter plaque fate by changing both the total quantity of lipid in the plaque and the distribution of lipid between the live cells, dead cells and necrotic core. The consequences of macrophage lipid-dependence are often unpredictable because lipid-dependent effects introduce subtle, nonlinear interactions between the modelled cell behaviours. These observations highlight the importance of mathematical modelling in unravelling the complexities of macrophage lipid accumulation during atherosclerotic plaque formation., (© 2023. The Author(s).)