Macrophage LRP-1 controls plaque cellularity by regulating efferocytosis and Akt activation.
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-1 beta, IL-6, and tumor necrosis factor-alpha 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.


CONCLUSIONS
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.
Yancey
Patricia G
PG
Division of Cardiology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA. patricia.g.yancey@vanderbilt.edu
Blakemore
John
J
Ding
Lei
L
Fan
Daping
D
Overton
Cheryl D
CD
Zhang
Youmin
Y
Linton
MacRae F
MF
Fazio
Sergio
S
D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects; D050197:Atherosclerosis / Q000201:enzymology* / Q000473:pathology; D002470:Cell Survival; D002478:Cells, Cultured; D004789:Enzyme Activation; D005260:Female; D020287:In Situ Nick-End Labeling; D007249:Inflammation / Q000201:enzymology* / Q000473:pathology; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008077:Lipoproteins, LDL / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009336:Necrosis; D010587:Phagocytosis / Q000187:drug effects; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
D001057:Apolipoproteins E; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008077:Lipoproteins, LDL; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D011973:Receptors, LDL; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; C099252:oxidized low density lipoprotein; D051057:Proto-Oncogene Proteins c-akt