Abstract
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 (104–) 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.
Highlights
Tissue homeostasis and inflammation resolution require macrophages to phagocytose pathogens and apoptotic cells, including their own apoptotic macrophages [1,2,3]
The experimental data are consistent with output from the mathematical model when (i) the initial condition of the model, i.e. the distribution of beads across the population, was equal to the experimental data, (ii) bead-loaded BMDMS stimulated with LPS and interferon g (IFNg) die with an average rate of 1/60 h21, (iii) there is no cell division, and (iv) apoptotic cells are consumed instantaneously
We hypothesized that cannibalistic efferocytosis contributes to the accumulation of substances inside inflammatory macrophages
Summary
Tissue homeostasis and inflammation resolution require macrophages to phagocytose pathogens and apoptotic cells (efferocytosis), including their own apoptotic macrophages (cannibalistic efferocytosis) [1,2,3]. Indigestible substances that transfer from animal-to-animal via predation can accumulate to toxic levels along food chains (a process called biomagnification) [22]. Conceivable, it is unknown if cannibalism and biomagnification have similar pathological consequences in macrophages as in animals. Do substances that transfer from cell-to-cell via cannibalistic efferocytosis (e.g. cholesterol and intracellular pathogens [15,17,18]) accumulate/biomagnify to potentially harmful levels inside macrophages?. Our experiments show that efferocytosis coalesces exogenous beads (derived from phagocytosis) and endogenous lipid (derived from the membranes of dead and consumed macrophages) inside murine macrophages following their stimulation into an inflammatory state ex vivo. Our results suggest that indigestible substances essentially biomagnify within inflammatory macrophage populations
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