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Modelling Preferential Phagocytosis in Atherosclerosis: Delineating Timescales in Plaque Development

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Abstract

Atherosclerotic plaques develop over a long time and can cause heart attacks and strokes. There are no simple mathematical models that capture the different timescales of rapid macrophage and lipid dynamics and slow plaque growth. We propose a simple ODE model for lipid dynamics that includes macrophage preference for ingesting apoptotic material and modified low-density lipoproteins (modLDL) over ingesting necrotic material. We use multiple timescale analysis to show that if the necrosis rate is small then the necrotic core in the model plaque may continue to develop slowly even when the lipid levels in plaque macrophages, apoptotic material and modLDL appear to have reached equilibrium. We use the model to explore the effect of macrophage emigration, apoptotic cell necrosis, total rate of macrophage phagocytosis and modLDL influx into the plaque on plaque lipid accumulation.

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References

  • Bäck M, Yurdagul A, Tabas I, Öörni K, Kovanen P (2019) Inflammation and its resolution in atherosclerosis: mediators and therapeutic opportunities. Nat Rev Cardiol 16:389–406

    Google Scholar 

  • Flores A, Hosseini-Nassab N, Jarr KU, Ye J, Zhu X, Wirka R, Koh A, Tsantilas P, Wang Y, Nanda V, Kojima Y, Zeng Y, Lotfi M, Sinclair R, Weissman I, Ingelsson E, Smith B, Leeper N (2020) Pro-efferocytic nanoparticles are specifically taken up by lesional macrophages and prevent atherosclerosis. Nat Nanotechnol 15(2):154

    Article  Google Scholar 

  • Ford H, Byrne H, Myerscough M (2019) A lipid-structured model for macrophage populations in atherosclerotic plaques. J Theor Biol 479:48–63

    Article  MathSciNet  Google Scholar 

  • Ford H, Zeboudj L, Purvis G, ten Bokum A, Zarebski A, Bull J, Byrne H, Myerscough M, Greaves D (2019) Efferocytosis perpetuates substance accumulation inside macrophage populations. Proc R Soc B Biol Sci 286(1904):20190730

    Article  Google Scholar 

  • Khan M, Pelegaris S, Cooper M, Smith C, Evan G, Betteridge J (2003) Oxidised lipoproteins may promote inflammation through the selective delay of engulfment but not binding of apoptotic cells by macrophages. Atherosclerosis 171:21–29

    Article  Google Scholar 

  • Kojima Y, Weissman I, Leeper N (2017) The role of efferocytosis in atherosclerosis. Circulation 135:476–489

    Article  Google Scholar 

  • Libby P (2002) Inflammation in atherosclerosis. Nature 420(6917):868–874

    Article  Google Scholar 

  • Llodrá J, Angeli V, Liu J, Trogan E, Fisher EA, Randolph GJ (2004) Emigration of monocyte-derived cells from atherosclerotic lesions characterizes regressive, but not progressive plaques. Proc Natl Acad Sci USA 101(32):11779–11784

    Article  Google Scholar 

  • Meunier N, Muller N (2019) Mathematical study of an inflammatory model for atherosclerosis: a nonlinear renewal equation. Acta Appl Math 161(1):107–126

    Article  MathSciNet  Google Scholar 

  • Moore K, Sheedy F, Fisher E (2003) Macrophages in atherosclerosis: a dynamic balance. Nat Rev Immunol 13:710–721

    Google Scholar 

  • Schrijvers D, De Meyer G, Herman A (2007) Phagocytosis in atherosclerosis: molecular mechanisms and implications for plaque progression and stability. Cardiovasc Res 73:470–480

    Article  Google Scholar 

  • Swirski F, Libby P, Aikawa E, Alcaide P, Luscinskas F, Weissleder R, Pittet M (2006) Ly-6C(hi) monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata. J Clin Investig 117(1):195–205

    Article  Google Scholar 

  • Tabas I (2005) Consequences and therapeutic implications of macrophage apoptosis in atherosclerosis. The importance of lesion stage and phagocytic efficiency. Arterioscler Thromb Vasc Biol 25:2255–2264

    Article  Google Scholar 

  • Tabas I (2010) Macrophage death and defective inflammation resolution in atherosclerosis. Nat Rev Immunol 10:36–46

    Article  Google Scholar 

  • Thon M, Ford H, Gee M, Myerscough M (2018) A quantitative model of early atherosclerotic plaques parameterized using in vitro experiments. Bull Math Biol 80:175–214

    Article  MathSciNet  Google Scholar 

  • Thorp E, Tabas I (2009) Mechanisms and consequences of efferocytosis in advanced atherosclerosis. J Leukoc Biol 86:1089–1095

    Article  Google Scholar 

  • van Gils J, Derby M, Fernandes L, Ramkhelawon B, Ray T, Rayner K, Parathath S, Distel E, Feig J, Alvarez-Leite J, Rayner A, McDonald T, O’Brien K, Stuart L, Fisher E, Lacy-Hulbert A, Moore K (2011) The neuroimmune guidance cue netrin-1 promotes atherosclerosis by inhibiting the emigration of macrophages from plaques. Nat Immunol 13(5):136–143

    Google Scholar 

  • Wentzel J, Chatzizisis Y, Gijsen F, Giannoglou G, Feldman C, Stone P (2012) Endothelial shear stress in the evolution of coronary atherosclerotic plaque and vascular remodelling: current understanding and remaining questions. Cardiovasc Res 96(2):234–243

    Article  Google Scholar 

  • Zhu X, Lee JY, Timmins J, Brown J, Boudyguina E, Mulya A, Gebre A, Willingham M, Hiltbold E, Mishra N, Maeda N, Parks J (2008) Increased cellular free cholesterol in macrophage-specific Abca1 knock-out mice enhances pro-inflammatory response of macrophages. J Biol Chem 283:22930–22941

    Article  Google Scholar 

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Correspondence to Mary R. Myerscough.

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MRM acknowledges funding from two Discovery Grants, DP160104685 and DP200102071, from the Australian Research Council.

Celebrating J.D. Murray’s Contributions to Mathematical Biolog.

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Lui, G., Myerscough, M.R. Modelling Preferential Phagocytosis in Atherosclerosis: Delineating Timescales in Plaque Development. Bull Math Biol 83, 96 (2021). https://doi.org/10.1007/s11538-021-00926-z

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  • DOI: https://doi.org/10.1007/s11538-021-00926-z

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