Colony stimulating factor 1 receptor (Csf1r) expressing cell ablation in mafia (macrophage-specific Fas-induced apoptosis) mice alters the monocyte landscape and characteristics of atherosclerotic lesions

Here we studied the impact of myeloid cell depletion on atherosclerosis in Apoe
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^/− mice using a Macrophage Fas-induced apoptosis (MaFIA) mouse model. MaFIA mice carry an inducible apoptosis gene under the control of the Csf1r promoter, who specifically and temporarily exhausts Csf1r-cells. Systemic induction of apoptosis reduced plaque macrophage and smooth muscle cell content without affecting plaque or necrotic core size. Interestingly, myeloid cell replenishment was associated with extramedullary myelopoiesis and a shift in circulating monocyte subsets. In contrast, local apoptosis induction reduced plaque burden and macrophage content with minimal impact on circulating myeloid cells.

Abstract

Macrophage infiltration and accumulation in the atherosclerotic lesion are associated with plaque progression and instability. Depletion of macrophages from the lesion may provide valuable insights into plaque stabilization processes. Therefore, we assessed the effects of systemic and local macrophage depletion on atherogenesis. To deplete monocytes/macrophages, we used atherosclerosis-prone Apoe⁻

^/− mice carrying a MaFIA (macrophage-Fas-induced-apoptosis) suicide construct under the control of the Csf1r (CD115) promoter, in which selective apoptosis of Csf1r-expressing cells was induced in a controlled manner, by administration of a drug, AP20187. Systemic induction of apoptosis resulted in a decrease in lesional macrophages and smooth muscle cells. Plaque size and necrotic core size were unaffected. Two weeks after systemic depletion of macrophages, we observed a replenishment of the myeloid compartment. Myelopoiesis was modulated resulting in an expansion of CSF1R^see myeloid cells in the circulation and a shift of Ly6c^Hi monocytes to Ly6c^int and Ly6c^see populations in the spleen. Local apoptosis induction led to a decrease in plaque burden and macrophage content with marginal effects on circulating myeloid cells. Local, but not systemic, depletion of Csf1r
⁺ myeloid cells resulted in reduced plaque burden. Systemic depletion led to CSF1R^see– expansion of monocytes in the blood, which may explain the lack of effects on plaque development.