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. LRP1 and its ligand, apoE, have been implicated in efferocytosis and apoptosis in some cell types. We investigated the involvement of the macrophage LRP1/apoE axis in controlling plaque apoptosis and efferocytosis. Method and Results LRP1-/- macrophages displayed nearly 2-fold more TUNEL positivity compared to WT cells in the presence of DMEM alone or with either LPS or oxidized LDL. The survival kinase, pAkt, was barely detectable in LRP1-/- cells, causing decreased pBad and increased cleaved caspase-3. Regardless of the apoptotic stimulation and degree of cell death, LRP1-/- macrophages displayed enhanced inflammation with increased IL-1β, IL-6, and TNFα expression. Efferocytosis of apoptotic macrophages was reduced by 60% in LRP1-/- versus WT macrophages despite increased apoE expression by both LRP1-/- phagocytes and WT apoptotic cells. Compared to WT macrophage lesions, LRP1-/- lesions had 5.7-fold more necrotic core with more dead cells not associated with macrophages. Conclusion Macrophage LRP1 deficiency increases cell death and inflammation by impairing pAkt activation and efferocytosis. Increased apoE expression in LRP1-/- macrophages suggests that the LRP1/apoE axis regulates the balance between apoptosis and efferocytosis thereby preventing necrotic core formation.

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“…LRP1 is another lipoprotein receptor involved in apoE metabolism. We previously reported that apoE-LRP1 interactions in macrophages control the rate of apoE secretion ( 51 ). We show that apoE Sendai has impaired binding to LRP1 and, as …”

An AXL/LRP-1/RANBP9 complex mediates DC efferocytosis and antigen cross-presentation in vivo

“…However, further studies will be needed to define if and how AC binding trig- Efferocytosis prevents secondary necrosis of ACs, and defects in efferocytosis have been linked to pathological tissue necrosis, such as that in the necrotic cores of advanced, clinically dangerous atherosclerotic lesions (47). For example, deletion of the macrophage efferocytosis receptors MERTK and LRP-1 have been demonstrated to exacerbate necrotic core formation in mouse models of advanced atherosclerosis (19,48,49). Interestingly, observational studies have shown that the necrotic cores of clinically dangerous human atheromata are often surrounded by mature DCs, which are relatively inefficient efferocytes that can constitute up to 30% of the phagocyte population of atherosclerotic lesions (7,50,51).…”

“…We next explored LRP-1, which has previously been implicated in efferocytosis by macrophages, but not DCs (18,19). Inhibition of LRP-1 by i.v.…”

Cathepsin G deficiency decreases complexity of atherosclerotic lesions in apolipoprotein E-deficient mice

“…Rodger P. McEver and Bojing Shao, Oklahoma Medical Research Foundation) as described above and cultured for 7 days. Effercytosis experiments were performed in a similar manner as previously described (32 BMDM (5 ϫ 10 5 cells/well) for 2 h before the phagocytes were washed vigorously four times with cold PBS before lysis in 0.1% Triton X-100. The fluorescence intensity of the lysates was determined by BioTek Synergy plate reader and corresponds to the degree of engulfment of CFDA SE-labeled apoptotic macrophages.…”