A lipid-structured model for macrophage populations in atherosclerotic plaques

Ford, Hugh Z; Byrne, Helen; Myerscough, Mary R.

doi:10.1101/557538

Cited by 2 publications

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References 51 publications

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“…owing to inefficient efferocytosis), then the constituents of dead cells could be shared across multiple macrophages. This scenario will change how substances are distributed among macrophages and has been addressed in another modelling study (under review) [27].…”

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confidence: 99%

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Efferocytosis perpetuates substance accumulation inside macrophage populations

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In both cells and animals, cannibalism can transfer harmful substances from the consumed to the consumer. Macrophages are immune cells that consume their own dead via a process called cannibalistic efferocytosis. Macrophages that contain harmful substances are found at sites of chronic inflammation, yet the role of cannibalism in this context remains unexplored. Here we take mathematical and experimental approaches to study the relationship between cannibalistic efferocytosis and substance accumulation in macrophages. Through mathematical modelling, we deduce that substances which transfer between individuals through cannibalism will concentrate inside the population via a coalescence process. This prediction was confirmed for macrophage populations inside a closed system. We used image analysis of whole slide photomicrographs to measure both latex microbead and neutral lipid accumulation inside murine bone marrow-derived macrophages (10 4 – 10 5 cells ) following their stimulation into an inflammatory state ex vivo . While the total number of phagocytosed beads remained constant, cell death reduced cell numbers and efferocytosis concentrated the beads among the surviving macrophages. As lipids are also conserved during efferocytosis, these cells accumulated lipid derived from the membranes of dead and consumed macrophages (becoming macrophage foam cells). Consequently, enhanced macrophage cell death increased the rate and extent of foam cell formation. Our results demonstrate that cannibalistic efferocytosis perpetuates exogenous (e.g. beads) and endogenous (e.g. lipids) substance accumulation inside macrophage populations. As such, cannibalism has similar detrimental consequences in both cells and animals.

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Section: Discussionmentioning

confidence: 99%

“…neutral lipids) into the tissue which fuel their accumulation inside monocyte-derived macrophages via efferocytosis. We have extended the mathematical model presented here to model these type of effects on lipid accumulation inside macrophages during artery wall inflammation associated with atherosclerosis (under review) [27].…”

Section: Discussionmentioning

confidence: 99%

Efferocytosis perpetuates substance accumulation inside macrophage populations

et al. 2019

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Efferocytosis perpetuates substance accumulation inside macrophage populations

Ford

Zeboudj

Purvis

et al. 2019

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Declaration of interest: NoneTissue homeostasis and inflammation resolution require macrophages to phagocytose pathogens 2 and apoptotic cells (efferocytosis), including their own apoptotic macrophages (cannibalistic effero-3 cytosis) [1][2][3]. Tissues that accumulate harmful stimuli (e.g. pathogens and necrotic cells) become 4 inflamed and populated by large numbers of macrophages and other immune cells. Macrophage 5 numbers increase via the recruitment and differentiation of monocytes from the bloodstream, and 6 the proliferation of tissue-resident or monocyte-derived macrophages; they decrease via apoptosis 7 (primarily) and emigration from the tissue [4][5][6][7]. Macrophages regulate inflammation via cytokine 8 signalling and phagocytosis. These processes are primarily mediated by cytoplasmic or cell-surface 9 pattern recognition receptors (PRRs) that detect pathogen-and damage-associated molecular pat-10 terns (PAMP/DAMPs) of pathogens and damaged cells [8]. In the presence of PAMP/DAMPs and 11 cytokines, macrophages polarise into a spectrum of pro-and anti-inflammatory states (e.g. M1 and 12 M2) and produce cytokines that orchestrate inflammation amplification and resolution [9][10][11]. The 13 persistence of PAMP/DAMPs in the tissue or inside macrophages can cause chronic inflammation 14 associated with disease [12][13][14]. The accumulation of pathogens and sterile substances inside mac-15 rophages is a hallmark of a variety of inflammatory diseases [15][16][17][18][19]. For example: Mycobacterium 16 tuberculosis infections [20], neutral lipids and cholesterol crystals during atherosclerosis [16, 21, 17 22], monosodium urate and calcium pyrophosphate dihydrate crystals during gout and pseudogout 18 [17], amyloid-β during Alzheimer's disease [18] and silica and asbestos during inflammation of the 19 lung [19, 23]. 20 21Inflammatory macrophages are short lived phagocytes and, as such, gain substances (e.g. patho-22 gens) from the dead macrophages which they consume, i.e., via cannibalistic efferocytosis [20, 24, 23 25]. Cannibalism, as seen in tumours, can be a beneficial mechanism that allows organisms to 24 scavenge nutrients when the supply is low [26][27][28]. However, as seen in ecosystems, cannibalism 25 can also transfer harmful substances (e.g. pathogens) between individuals, potentially allowing 26 them to reach toxic levels inside individuals [29]. As such, cannibalism can perpetuate disease 27 transmission in both cell systems (e.g. tuberculosis [20, 24]) and ecosystems (e.g. Kuru neurode-28 generative disorder and bovine spongiform encephalopathy [30]). It is conceivable that cannibalism 29 might play a broad pathological role in macrophages as it does across the animal kingdom. 30 31In this study we use experimental and mathematical approaches to elucidate the relationship 32 between cannibalitic efferocytosis and substance accumulation in macrophages. We observe that 33 efferocytosis fuses the contents of two macrophages into one whereas division splits the contents 34 of one macrophage...

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A lipid-structured model for macrophage populations in atherosclerotic plaques

Abstract: Declarations of interest: none.

Cited by 2 publications

References 51 publications

Efferocytosis perpetuates substance accumulation inside macrophage populations

Efferocytosis perpetuates substance accumulation inside macrophage populations

Efferocytosis perpetuates substance accumulation inside macrophage populations

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