In the setting of hypercholesterolemia or defects in cholesterol efflux,
hematopoietic stem and progenitor cells (HSPCs) accumulate excess cholesterol.
The consequence is enhanced IL-3 and GM-CSF growth factor signaling, leading to
HSPC proliferation and monocytosis. With aging, clonal hematopoiesis can occur
owing to loss-of-function mutations in a number of genes, including
TET2. This process also contributes to monocytosis.
Monocytosis is associated with increased accumulation of inflammatory
monocyte-derived macrophages in atherosclerotic lesions and higher risk of
atherosclerotic vascular disease in humans. These lesional macrophages are also
subject to intracellular cholesterol accumulation owing to their internalization
of subendothelial apoB LPs. Excess cholesterol in macrophages has multiple
effects that enhance lesion inflammation, including toll-like receptor (TLR) and
inflammasome activation. The result is increased production of inflammatory
chemokines and cytokines, including inflammasome-derived IL-1β and
IL-1β-induced IL-6 production. Moreover, changes associated with clonal
hematopoiesis, e.g., loss of TET2 function, can also activate
the inflammasome in macrophages, further fueling lesional inflammation. T cells
do not have the capacity to accumulate large amounts of excess cholesterol, but
several studies have shown that perturbations of T cell cholesterol metabolism
can affect T cell differentiation and activation. Impaired ABCG1 cholesterol
efflux from T cells results in enhanced Treg differentiation which reduces
atherosclerotic lesion development and inflammation. In contrast, impaired
esterification of cholesterol by deficiency or inhibition of acyl-coenzyme
A:cholesterol acyltransferase (ACAT) increases CD8 effector T cell lipid raft
formation and thereby enhances immune synapse formation and killing functions of
these cells. The net effect of increases in T cell cholesterol on lesion
development and inflammation are likely to reflect changes in the Teff:Treg
balance and the influence of Teff cells on lesional macrophages.