The LRP1/CD91 ligands, tissue-type plasminogen activator, α2-macroglobulin, and soluble cellular prion protein have distinct co-receptor requirements for activation of cell-signaling

LDL Receptor-related Protein-1 (LRP1/CD91) binds diverse ligands, many of which activate cell-signaling. Herein, we compared three LRP1 ligands that inhibit inflammatory responses triggered by lipopolysaccharide (LPS), including: enzymatically-inactive tissue-type plasminogen activator (EI-tPA); activated alpha(2)-macroglobulin (alpha M-2); and S-PrP, a soluble derivative of nonpathogenic cellular prion protein (PrPc). In bone marrow-derived macrophages, the N-methyl-D-aspartate receptor was essential for all three LRP1 ligands to activate cell-signaling and inhibit LPS-induced cytokine expression. Intact lipid rafts also were essential. Only alpha M-2 absolutely required LRP1. LRP1 decreased the EI-tPA concentration required to activate cell-signaling and antagonize LPS but was not essential, mimicking its role as a S-PrP co-receptor. Membrane-anchored PrPc also functioned as a co-receptor for EI-tPA and alpha M-2, decreasing the ligand concentration required for cell-signaling and LPS antagonism; however, when the concentration of EI-tPA or alpha M-2 was sufficiently increased, cell-signaling and LPS antagonism occurred independently of PrPc. S-PrP is the only LRP1 ligand in this group that activated cell-signaling independently of membrane-anchored PrPc. EI-tPA, alpha M-2, and S-PrP inhibited LPS-induced LRP1 shedding from macrophages, a process that converts LRP1 into a pro-inflammatory product. Differences in the co-receptors required for anti-inflammatory activity may explain why LRP1 ligands vary in ability to target macrophages in different differentiation states.

Automated summary

In this study, we compared three ligands of LRP1 that inhibit inflammatory responses triggered by LPS. These ligands activate cell signaling and require N-methyl-D-aspartate receptor and intact lipid rafts. Among them, alpha M-2 is the only ligand that absolutely requires LRP1, while S-PrP can activate cell signaling independently of membrane-anchored PrPc.