Abstract 19057: Macrophage SR-BI Deletion Promotes Defective Efferocytosis via Src/Akt/Rac1 Signaling Pathway Resulting in Increased Atherosclerotic Lesion Necrosis
Apolipoprotein E (ApoE) and scavenger receptor class B type I (SR-BI) double knockout (DKO) mice exhibit accelerated coronary atherosclerosis and premature death, but the underlying mechanisms have not been fully elucidated. Defective phagocytosis of apoptotic cells (efferocytosis) is an important mechanism behind increased necrosis and inflammation in atherosclerosis. We performed bone marrow transplantation studies in apoE-/- mice to examine the impact of macrophage deficiency of SR-BI on atherosclerotic lesion cell death, efferocytosis, and inflammation. DKO→ApoE-/- mice developed 2.1-fold more atherosclerotic lesion area (P<0.01) with 6.7-fold more apoptotic cells (P<0.01), and 5.2-fold higher necrotic core content (P<0.01), compared to ApoE-/-SRBI+/+→ApoE-/- mice. Efferocytosis was dramatically defective as shown by a 17-fold higher ratio of free to macrophage associated apoptotic nuclei/bodies in atherosclerotic lesions of DKO→ApoE-/- mice(P<0.01). Deletion of macrophage SR-BI resulted in 64.3% (P<0.01) and 64.2 % (P<0.01) decreases in efferocytosis of apoptotic WT thymocytes compared to WT macrophages in vitro and in vivo, respectively. Deletion of macrophage SR-BI elicited maladaptive inflammation with significantly higher expression of pro-inflammation genes (IL-1β, IL-6, TNF-α) and lower expression of anti-inflammation genes (IL-10 and TGF-β). Moreover, SR-BI bound phosphatidylserine in vitro and on the surface of apoptotic cells. SR-BI directly interacted with Src in macrophages. SR-BI deficiency caused significant decreases in Src/Akt/Rac1 activities during macrophage efferocytosis of apoptotic cells. Pharmacological activation of Rac1 rescued SR-BI deficiency-mediated defective efferocytosis, and inhibition of Src reduced macrophage efferocytosis. In conclusion, macrophage SR-BI deficiency promotes defective efferocytosis resulting in increased atherosclerotic lesion necrosis and maladaptive inflammation. Thus, macrophage SR-BI functions as a receptor for apoptotic cells and mediator of efferocytosis via the Src/Rac1 signaling pathway, supporting macrophage SR-BI expression and signaling as a potential target for the prevention and treatment of atherosclerosis.
- © 2013 by American Heart Association, Inc.