Theory and experiments on cannibalism in macrophages

Abstract

In this thesis I use mathematical and experimental approaches to show that cannibalistic efferocytosis (where cells consume dead cells of the same type) perpetuates the accumulation of particles inside macrophages. We deduce that particles which are transferred between individuals through cannibalism will concentrate inside the population via a coalescence process. We model this process using a coagulation-fragmentation equation (a system of ordinary differential equations). This time-dependent solution to a simplified version of this model is solved analytically. We confirm this prediction experimentally for macrophage populations inside a closed system. We use image analysis of whole slide photomicrographs to measure both latex microbead and neutral lipid accumulation inside murine bone marrow-derived macrophages following their ex vivo stimulation into an inflammatory state. While the total number of phagocytosed beads remained constant, cell death reduced cell numbers and efferocytosis concentrated the beads among the surviving macrophages. Since lipids are also conserved during efferocytosis, these cells accumulated lipid derived from the membranes of dead and consumed macrophages (becoming macrophage foam cells). Our results demonstrate that cannibalistic efferocytosis perpetuates exogenous (e.g. beads) and endogenous (e.g. lipids) substance accumulation inside macrophage populations. We extend our experimentally-verified coagulation-fragmentation equation to study lipid accumulation inside macrophages during inflammation associated with atherosclerosis. Atherosclerosis is a chronic inflammatory disease orchestrated by macrophages in the artery wall which accumulate lipid. This model includes a lipid-structured partial integro-differential equation. The steady state solution to this equation can be found and used to understand several aspects of atherosclerosis.