Journal
SCIENTIFIC REPORTS
Volume 12, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41598-022-22498-1
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- National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH) [R01 HL136395]
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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.
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.
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