ApoA-I deletion in apoE-KO mice promotes massive cholesterol accumulation and inflammation in skin and skin-draining lymph nodes

Background. Previous experimental findings demonstrate that diet-induced hypercholesterolemia, in atherosclerosis-prone mice lacking apoA-I, leads to a massive accumulation of cholesterol in skin and skin-draining lymph nodes. Aim. To determine how apoA-I could affect skin and skin-draining lymph nodes morphology and composition of athero-prone mice in normocholesterolemic conditions. Methods. C57Bl/6 (WT), apoE-KO (EKO), apoA-I-deficient/apoE-KO (dKO) or dKO overexpressing human apoA-I (hA-I) mice were fed a chow diet for 30 weeks. Plasma cholesterol concentration and distribution among lipoproteins were evaluated. Skin biopsies were processed for light microscopy and transmission electron microscopy. Histology and lipid deposition in axillary/inguinal skin-draining lymph nodes were also characterized. Results. Plasma total cholesterol concentration in dKO mice was comparable with that of WT mice and 3-fold lower than the concentration observed in EKO and hA-I mice. Cholesterol in WT mice was almost exclusively confined to the HDL fraction whereas in EKO mice an elevated cholesterol accumulation in VLDL/LDL and low HDL levels were observed. In dKO mice, HDL cholesterol was absent and cholesterol accumulation in the VLDL/LDL fractions was lower than that found in EKO mice. hA-I mice were characterized by a less prominent presence of VLDL/LDL, but a larger HDL cholesterol peak than that found in EKO mice. Skin morphology of EKO and hA-I mice was comparable with that of WT mice. Conversely, dKO mouse skin was characterized by increased dermal thickness, accumulation of foam cells and lymphocytes. Additionally, electron microscopy highlighted the presence of cholesterol crystals both in the extracellular milieu and within foamy macrophages. dKO mice also had enlarged axillary and inguinal skin-draining lymph nodes, characterized by the accumulation of foamy macrophages, increased cholesterol and lipid deposition, together with the presence of cholesterol crystals surrounded by granulomatous reactions, and dilated sinuses. Conclusions. Our study demonstrates that HDL/apoA-I deficiency itself, in the absence of hyperlipidemia, is sufficient to induce an aberrant accumulation of cholesterol with a concomitant infiltration of foamy macrophages and lymphocytes in the skin and in axillary/inguinal skin-draining lymph nodes.