Fragmented uptake drives lipid accumulation in macrophage cannibalistic efferocytosis

RESUMO

Efferocytosis, the clearance of dying cells typically by macrophages, is essential for tissue homeostasis and the resolution of inflammation. Previous experiments by Ford et al. (Proc. R. Soc. B, 2019) showed that cannibalistic efferocytosis redistributes endogenous lipid from dying macrophages into the surviving population, but existing mathematical models do not reproduce the observed population dynamics and lipid distributions. Here, fifteen candidate models are compared, combining three mechanisms of apoptotic material uptake with five forms of the macrophage death rate. Model comparison is guided by the Akaike Information Criterion and qualitative agreement with the observed lipid distributions. Numerical solutions show that whole-cell uptake models predict internal maxima that are absent from the data, whereas nibbling uptake produces distributions that are too concentrated about their means. By contrast, intermediate "fragmented" uptake models provide substantially improved agreement when combined with either linear lipid-dependent or exponential time-dependent death rates. The fitted models predict that smaller fragments from dying cells are ingested at higher frequency than larger ones. This analysis provides new insight into how efferocytosis shapes the distribution of lipid within macrophage populations and highlights the importance of distribution-level data for distinguishing between mechanistic models that reproduce similar population-average dynamics.