Macrophage LRP-1 Controls Plaque Cellularity by Regulating Efferocytosis and Akt Activation

Abstract

Objective— The balance between apoptosis susceptibility and efferocytosis of macrophages is central to plaque remodeling and inflammation. LRP-1 and its ligand, apolipoprotein E, have been implicated in efferocytosis and apoptosis in some cell types. We investigated the involvement of the macrophage LRP-1/apolipoprotein E axis in controlling plaque apoptosis and efferocytosis. Method and Results— LRP-1 −/− macrophages displayed nearly 2-fold more TUNEL positivity compared to wild-type cells in the presence of DMEM alone or with either lipopolysaccharide or oxidized low-density lipoprotein. The survival kinase, phosphorylated Akt, was barely detectable in LRP-1 −/− cells, causing decreased phosphorylated Bad and increased cleaved caspase-3. Regardless of the apoptotic stimulation and degree of cell death, LRP-1 −/− macrophages displayed enhanced inflammation with increased IL-1β, IL-6, and tumor necrosis factor-α expression. Efferocytosis of apoptotic macrophages was reduced by 60% in LRP-1 −/− vs wild-type macrophages despite increased apolipoprotein E expression by both LRP-1 −/− phagocytes and wild-type apoptotic cells. Compared to wild-type macrophage lesions, LRP-1 −/− lesions had 5.7-fold more necrotic core with more dead cells not associated with macrophages. Conclusion— Macrophage LRP-1 deficiency increases cell death and inflammation by impairing phosphorylated Akt activation and efferocytosis. Increased apolipoprotein E expression in LRP-1 −/− macrophages suggests that the LRP-1/apolipoprotein E axis regulates the balance between apoptosis and efferocytosis, thereby preventing necrotic core formation.