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

Abstract

Glucose-regulated protein-78 (Grp78) is an endoplasmic reticulum chaperone, which is secreted by cells and associates with cell surfaces, where it functions as a receptor for activated α 2 -macroglobulin (α 2 M) and tissue-type plasminogen activator (tPA). In macrophages, α 2 M and tPA also bind to the transmembrane receptor, LDL receptor-related protein-1 (LRP1), activating a cell-signaling receptor assembly that includes the NMDA receptor (NMDA-R) to suppress innate immunity. Herein, we demonstrate that an antibody targeting Grp78 (N88) inhibits NFκB activation and expression of proinflammatory cytokines in bone marrow-derived macrophages (BMDMs) treated with the toll-like receptor-4 (TLR4) ligand, lipopolysaccharide, or with agonists that activate TLR2, TLR7, or TLR9. Pharmacologic inhibition of the NMDA-R or deletion of the gene encoding LRP1 (Lrp1) in BMDMs neutralizes the activity of N88. The fibrinolysis protease inhibitor, plasminogen activator inhibitor-1 (PAI1), has been implicated in diverse diseases including metabolic syndrome, cardiovascular disease, and type 2 diabetes. Deletion of Lrp1 independently increased expression of PAI1 and PAI2 in BMDMs, as did treatment of wild-type BMDMs with TLR agonists. tPA, α 2 M, and N88 inhibited expression of PAI1 and PAI2 in BMDMs treated with TLR-activating agents. Inhibiting Src family kinases blocked the ability of both N88 and tPA to function as anti-inflammatory agents, suggesting that the cell-signaling pathway activated by tPA and N88, downstream of LRP1 and the NMDA-R, may be equivalent. We conclude that targeting cell-surface Grp78 may be effective in suppressing innate immunity by a mechanism that requires LRP1 and the NMDA-R.

HIST1H2BK predicts neoadjuvant-chemotherapy response and mediates 5-fluorouracil resistance of gastric cancer cells

“…5 D). Since LRP1 and GRP78 was the main receptors of A2M to activate PI3K/Akt signaling pathway [ [30] , [31] , [32] , [33] ], we assessed that A2M was positively associated with LRP1 but passively associated with GRP78 in GC using GEPIA database ( Fig. 5 E-F).…”

“…However, the mechanisms underlying A2M-mediated chemoresistance remain unexplored. A2M always binds to LRP1 or GRP78 and then performs its biological functions [ 30 , 31 ]. LRP1 and GRP78 decreased chemotherapy-induced apoptosis and promoted chemoresistance through the activation of PI3K/Akt signaling pathway [ 32 , 33 ].…”

Recent Advances of Proteomics in Management of Acute Kidney Injury

“…This so called ‘selectivity’ of α 2 M protein is based on the presence of a polypeptide ‘target’ region in the chemical structure of α 2 M which became attractive for most of the proteolytic peptidases [ 96 , 97 , 98 , 99 ]. In the past, most of the studies related to α 2 M role were focused in exploring hemostasis and thrombosis as critical conditions for patients in intensive care units (ICUs) [ 100 , 101 ]. However, upregulated α 2 M levels have also been associated with other serious chronic diseases: kidney-related and cardiovascular related diseases [ 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 ].…”

An LRP1-binding motif in cellular prion protein replicates cell-signaling activities of the full-length protein

“…In addition to membrane-anchored PrP C , the LRP1/NMDA-R assembly may associate with other proteins to trigger cell signaling. For example, the endoplasmic reticulum chaperone, Grp78, associates with LRP1 when released by cells and may participate in activation of cell signaling via the LRP1/NMDA-R assembly ( 61 , 62 ). Other receptors that interact with PrP C to mediate cell-signaling events include NCAM, mGluR5, and Adgrg6/gpr126 ( 63 – 65 ).…”