Modelling Preferential Phagocytosis in Atherosclerosis: Delineating Timescales in Plaque Development

Lui, Gigi; Myerscough, Mary R.

doi:10.1007/s11538-021-00926-z

Cited by 13 publications

(13 citation statements)

References 16 publications

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“…Hence the number of live macrophages may be a poor indicator of early plaque progression when not considered simultaneously with information about plaque lipid content. These observations are also consistent with the work of Lui and Myerscough Lui and Myerscough (2021), and likely manifest due to preferential uptake of apoptotic lipid over necrotic lipid by live macrophages (the assumption θ < η in our model).…”

Section: Discussionsupporting

confidence: 91%

A lipid-structured mathematical model of atherosclerosis with macrophage proliferation

Chambers¹,

Watson²,

Myerscough³

2022

Preprint

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We extend the lipid-structured model for atherosclerotic plaque development of Ford et al (2019) to account for macrophage proliferation. Proliferation is modelled as a non-local decrease in the lipid structural variable that is similar to the treatment of cell division in size-structured models (e.g. Efendiev et al ( 2018)). Steady state analysis indicates that proliferation assists in reducing eventual necrotic core size and acts to spread the lipid load of the macrophage population amongst the cells. The relative contribution of plaque macrophages by proliferation and recruitment from the bloodstream is also examined. The model suggests that a more proliferative plaque differs from an equivalent (same lipid content and cell count) recruitment-dominant plaque only in the way lipid is distributed amongst the macrophages.

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Section: Discussionsupporting

confidence: 91%

A lipid-structured mathematical model of atherosclerosis with macrophage proliferation

Chambers¹,

Watson²,

Myerscough³

2022

Preprint

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“…Much of this work uses a continuum approach to investigate the activity of monocytes and macrophages in the vessel wall and their interactions with lipoproteins. Previous work in our group has considered the accumulation and efferocytic clearance of apoptotic cells using both ODE models (Lui and Myerscough 2021 ) and non-spatial lipid-structured PDE models for macrophage populations in plaques (Ford et al 2019 ; Chambers et al 2022 ). An alternative model by Fok ( 2012 ) considers macrophages and dead cells in a reaction-diffusion model for plaque development.…”

Section: Introductionmentioning

confidence: 99%

Macrophage Anti-inflammatory Behaviour in a Multiphase Model of Atherosclerotic Plaque Development

2023

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Atherosclerosis is an inflammatory disease characterised by the formation of plaques, which are deposits of lipids and cholesterol-laden macrophages that form in the artery wall. The inflammation is often non-resolving, due in large part to changes in normal macrophage anti-inflammatory behaviour that are induced by the toxic plaque microenvironment. These changes include higher death rates, defective efferocytic uptake of dead cells, and reduced rates of emigration. We develop a free boundary multiphase model for early atherosclerotic plaques, and we use it to investigate the effects of impaired macrophage anti-inflammatory behaviour on plaque structure and growth. We find that high rates of cell death relative to efferocytic uptake results in a plaque populated mostly by dead cells. We also find that emigration can potentially slow or halt plaque growth by allowing material to exit the plaque, but this is contingent on the availability of live macrophage foam cells in the deep plaque. Finally, we introduce an additional bead species to model macrophage tagging via microspheres, and we use the extended model to explore how high rates of cell death and low rates of efferocytosis and emigration prevent the clearance of macrophages from the plaque.

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“…Most work to date has focussed on modelling the inflammatory response of macrophages in the early plaque. Published approaches include spatiallyaveraged ODE models (Bulelzai and Dubbeldam, 2012;Cohen et al, 2014;Islam and Johnston, 2016;Thon et al, 2018;Lui and Myerscough, 2021), spatially-resolved PDE models (El Khatib et al, 2007;Calvez et al, 2009;Little et al, 2009;Yang et al, 2016;Chalmers et al, 2017;Thon et al, 2019;Silva et al, 2020) and agent-based models (Bhui and Hayenga, 2017). To account for macrophage lipid ingestion it is common to assume that the modelled macrophages have two sub-populations: those with little or no internalised lipid (usually termed macrophages) and those with lots of internalised lipid (usually termed foam cells) (Calvez et al, 2009;Bulelzai and Dubbeldam, 2012;Cilla et al, 2014;Hao and Friedman, 2014;Islam and Johnston, 2016;Yang et al, 2016;Chalmers et al, 2017;Silva et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

“…Lipid-dependent macrophage behaviour can be implicitly incorporated in this model framework by assuming that these sub-populations have, for example, different rates of lipid consumption (Calvez et al, 2009;Bulelzai and Dubbeldam, 2012;Cilla et al, 2014;Hao and Friedman, 2014;Islam and Johnston, 2016;Silva et al, 2020), migration (Calvez et al, 2009;Cilla et al, 2014;Yang et al, 2016;Chalmers et al, 2017;Silva et al, 2020) or apoptosis (Hao and Friedman, 2014;Islam and Johnston, 2016;Silva et al, 2020). An alternative approach is to model macrophages as a single population and track the population's total ingested lipid content (Little et al, 2009;Cohen et al, 2014;Thon et al, 2018Thon et al, , 2019Lui and Myerscough, 2021). Here, lipid-dependent effects can be included at the population-level by assuming that macrophage behaviour depends on the average ingested lipid load (Thon et al, 2018(Thon et al, , 2019.…”

Section: Introductionmentioning

confidence: 99%

A Lipid-Structured Model of Atherosclerotic Plaque Macrophages with Lipid-Dependent Kinetics

Watson¹,

Chambers²,

Myerscough³

2022

Preprint

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Atherosclerotic plaques are fatty growths in artery walls that cause heart attacks and strokes. Plaque formation is orchestrated by macrophages that are recruited to the artery wall to consume and remove blood-derived lipids, such as low-density lipoprotein (LDL). Ineffective lipid removal, due to macrophage death and other factors, leads to the accumulation of lipid-loaded macrophages and formation of a necrotic core. Experimental observations suggest that macrophage functionality varies with the extent of lipid loading. However, little is known about the resultant influence on plaque fate. Extending work by Ford et al. (2019a) and Chambers et al. ( 2022), we develop a plaque model in which macrophages are classified by their ingested lipid content and behave in a lipid-dependent manner. The model, a system of partial-integro differential equations, considers several macrophage behaviours. These include: recruitment to the artery wall; proliferation and apotosis; ingestion of LDL, apoptotic cells and necrotic lipid; emigration from the artery wall; and necrosis of apoptotic cells. Here, we consider apoptosis, emigration and proliferation to be lipid-dependent. We model lipid-dependence in these behaviours with experimentally-informed functions of the internalised lipid load. Our results demonstrate that lipiddependent 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. For lipid-dependent apoptosis and lipid-dependent emigration simulations, we find significant differences in outcomes for cases that ultimately converge on the same net rate of apoptosis or emigration.

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Modelling Preferential Phagocytosis in Atherosclerosis: Delineating Timescales in Plaque Development

Cited by 13 publications

References 16 publications

A lipid-structured mathematical model of atherosclerosis with macrophage proliferation

A lipid-structured mathematical model of atherosclerosis with macrophage proliferation

Macrophage Anti-inflammatory Behaviour in a Multiphase Model of Atherosclerotic Plaque Development

A Lipid-Structured Model of Atherosclerotic Plaque Macrophages with Lipid-Dependent Kinetics

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