High Density Lipoprotein Stimulated Migration of Macrophages Depends on the Scavenger Receptor Class B, Type I, PDZK1 and Akt1 and Is Blocked by Sphingosine 1 Phosphate Receptor Antagonists

Abstract

HDL carries biologically active lipids such as sphingosine-1-phosphate (S1P) and stimulates a variety of cell signaling pathways in diverse cell types, which may contribute to its ability to protect against atherosclerosis. HDL and sphingosine-1-phosphate receptor agonists, FTY720 and SEW2871 triggered macrophage migration. HDL-, but not FTY720-stimulated migration was inhibited by an antibody against the HDL receptor, SR-BI, and an inhibitor of SR-BI mediated lipid transfer. HDL and FTY720-stimulated migration was also inhibited in macrophages lacking either SR-BI or PDZK1, an adaptor protein that binds to SR-BI's C-terminal cytoplasmic tail. Migration in response to HDL and S1P receptor agonists was inhibited by treatment of macrophages with sphingosine-1-phosphate receptor type 1 (S1PR1) antagonists and by pertussis toxin. S1PR1 activates signaling pathways including PI3K-Akt, PKC, p38 MAPK, ERK1/2 and Rho kinases. Using selective inhibitors or macrophages from gene targeted mice, we demonstrated the involvement of each of these pathways in HDL-dependent macrophage migration. These data suggest that HDL stimulates the migration of macrophages in a manner that requires the activities of the HDL receptor SR-BI as well as S1PR1 activity.

Modification of HDL by reactive aldehydes alters select cardioprotective functions of HDL in macrophages

“…For example, oxLDL inhibits macrophage migration by promoting macrophage trapping , a process that helps mediate foam cell formation and pro‐inflammatory signaling. On the other hand, HDL promotes the migration of macrophages through an SR‐BI–dependent process . Therefore, we performed a Boyden Chamber assay to determine the impact of aldehyde modification on HDL’s ability to promote macrophage migration.…”

“…In macrophages, HDL also protects against the generation of ROS and promotes the production of anti‐inflammatory cytokines . Furthermore, by interacting with SR‐BI, HDL can promote macrophage migration and prevent foam cell formation (reviewed in ).…”

SR-BI: A Multifunctional Receptor in Cholesterol Homeostasis and Atherosclerosis

“…Furthermore, PI3K/Akt signaling in macrophages regulates NF-κB activation (Figure 3)[76, 79], and recent studies have shown that the interaction of macrophage SR-BI with apoptotic cells activates PI3K/Akt signaling (Figure 3) and induces expression of anti-inflammatory cytokines(Il-10, TGF-β)[11]. In addition, HDL activates PI3K/Akt signaling in macrophages, which is mediated by SR-BI and involves interaction with its adaptor protein, PDZK1(Box 1), and activation of S1P receptor 1(S1PR1) signaling[40]. Thus, a likely mechanism by which SR-BI regulates inflammation is by activating Akt phosphorylation leading to reduced NF-κB activation (Figure 3)[40].…”

“…In addition, HDL activates PI3K/Akt signaling in macrophages, which is mediated by SR-BI and involves interaction with its adaptor protein, PDZK1(Box 1), and activation of S1P receptor 1(S1PR1) signaling[40]. Thus, a likely mechanism by which SR-BI regulates inflammation is by activating Akt phosphorylation leading to reduced NF-κB activation (Figure 3)[40]. …”

“…PDZK1 interaction with SR-BI is not required for Src interaction with SR-BI, but is essential to Src activation[39]. In macrophages, PDZK1 is also required for HDL/SR-BI induced activation of Akt[40]. In hepatocytes, PDZK1 interaction maintains steady state levels of SR-BI by preventing its degradation[41].…”