Ox-LDL-induced CD80⁺ macrophages expand pro-atherosclerotic NKT cells via CD1d in atherosclerotic mice and hyperlipidemic patients

Abstract

Atherosclerosis is an inflammatory disease of blood vessels involving the immune system. Natural killer T (NKT) cells, as crucial components of the innate and acquired immune systems, play critical roles in the development of atherosclerosis. However, the mechanism and clinical relevance of NKT cells in early atherosclerosis are largely unclear. Our findings demonstrated that there were higher populations of NKT cells and interferon gamma (IFN-γ)-producing NKT cells in the peripheral blood of patients with hyperlipidemia and in the aorta, blood, spleen, and bone marrow of early atherosclerotic mice compared to control groups. Moreover, we discovered that the infiltration of M1 macrophages and CD1d expression on M1 macrophages in atherosclerotic mice climbed remarkably. CD1d expression increased in M1 macrophages stimulated by oxidized low-density lipoprotein (ox-LDL) ex vivo and in vitro. Ex vivo co-culture of macrophages with NKT cells revealed that ox-LDL-induced M1 macrophages presented lipid antigen alpha-galactosylceramide (α-Galcer) to NKT cells via CD1d, enabling NKT cells to express more IFN-γ. Furthermore, a greater proportion of CD1d+ monocytes and CD1d+ M1 monocytes were found in peripheral blood of hyperlipidemic patients compared with that of healthy donors. Positive correlations were found between CD1d+ M1 monocytes and NKT cells or IFN-γ+ NKT cells in hyperlipidemic patients. Our findings illustrate that M1 macrophages stimulate NKT cells to secret IFN-γ via CD1d presenting α-Galcer, which may accelerate the progression of early atherosclerosis. Inhibiting lipid antigen presentation by M1 macrophages to NKT cells may be a promising immune target for the treatment of early atherosclerosis.