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

Abstract

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 α2-macroglobulin (α2M); 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 α2M 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 α2M, decreasing the ligand concentration required for cell-signaling and LPS antagonism; however, when the concentration of EI-tPA or α2M 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, α2M, 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.

An antibody that targets cell‐surface glucose‐regulated protein‐78 inhibits expression of inflammatory cytokines and plasminogen activator inhibitors by macrophages

“…In addition to the NMDA‐R, the receptor assembly that activates anti‐inflammatory cell‐signaling in response to LRP1 ligands may include other proteins such as PrP C , which physically associates with LRP1 in lipid rafts 5,7,38 . In this study, we identified N88 as an antibody that has no apparent affinity for LRP1 but still counteracts TLR responses in macrophages by an LRP1 and NMDA‐R‐dependent pathway.…”

“…SFKs are calcium‐responsive enzymes 36,37 . SFK pharmacologic antagonism blocks the pathway by which EI‐tPA inhibits LPS‐induced cytokine expression in BMDMs 38 . Figure 5A shows that the SFK inhibitor, PP2, neutralized the activity of EI‐tPA as an inhibitor of LPS‐induced IκBα phosphorylation.…”

Association of Low Levels of Soluble Low-Density Lipoprotein Receptor-Related Protein-1 and COVID-19 Outcomes During the First Wave of Pandemic

“…The study included COVID-19 patients during the first wave of the pandemic. LRP1 is a poorly understood multifunctional receptor with a variety of structurally diverse ligands [ 6 , 7 ]. The first objective of this study is to compare the sLRP1 levels between COVID-19 patients and healthy controls.…”

“…Low-density lipoprotein receptor-related protein-1 (LRP1) is a large multifunctional receptor with a variety of structurally diverse ligands [ 6 , 7 ]. As one of the low-density lipoprotein receptor family, LRP1 is also known as the apolipoprotein E receptor [ 8 ].…”

“…The structure of LRP1 is composed of transmembrane and cytoplasmic domains [ 14 ]. LRP1 has a soluble form, which can be detected in the serum [ 7 , 15 ]. sLRP1 (soluble form) is composed of the α-chain and a fragment of the β chain [ 6 , 11 ].…”