ApoE and Macrophage Population Dynamics
However, we did note that macrophage population dynamics differed between the apoE-deficient mice and their wild-type littermate controls, suggesting that the apoE protein plays a hitherto unsuspected role in the regulation of macrophage numbers in a wide range of tissues. Analysis of macrophage population dynamics in apoE deficient mice revealed a surprising defect: live macrophages and newly recruited macrophages were both more common in a wide range of tissues (liver, skin, lung and brain) but there was a much bigger increase in the number of apoptotic (TUNEL+) macrophages, compared with wild-type mice. Careful analysis of the dynamics led to the conclusion that clearance of apoptotic cell remnants was impaired (but not abolished) in the absence of apoE (J. Immunol 173:6366). We went on to demonstrate that cultured peritoneal macrophages from apoE-deficient mice had a specific defect in the phagocytosis of apoptotic thymocytes, and that this defect (which resulted in more than a 50% decrease in the number of apoptotic cells taken up over an hour in culture) was reversed by the addition of exogenous apoE protein. An important consequence of this reduced ability to clear apoptotic debris is the need to recruit more macrophages into various tissues to "keep up with the housework". This, in turn, establishes a systemic pro-inflammatory condition with increased numbers of macrophages in many tissues, as well as higher levels of the pro-inflammatory cytokine TNF-alpha and the positive acute phase reactant fibrinogen. (J. Immunol 173:6366).
These observations provide an intriguing new hypoithesis to explain the association of apoE genotype with a wide range of diseases, including heart disease, Alzheimer's Disease and possibly also osteoporosis. We propose that the pathogenic apoE4 variant is slightly less functional than the wildtype E3 variant at promoting apoptotic cell clearance. Over a lifetime, this marginal deficiency leads to an accumulation of uncleared apoptotic cell remnants in various tissues, as well as the establishment of a subtle pro-inflammatory phenotype. Eventually, these two can combine to damage the tissue architecture, particularly in sensitive tissues such as the brain, to such an extent that functional deficits begin to appear. We are currently investigating the validity of this hypothesis, initially using apoE2, E3 and E4 in cell culture models of phagocytosis, but eventually also in transgenic mice lines expressing either human apoE2, E3 or E4 on a murine apoE-deficient background.