PMID- 36947703
OWN - NLM
STAT- MEDLINE
DCOM- 20230522
LR  - 20240502
IS  - 1097-4644 (Electronic)
IS  - 0730-2312 (Print)
IS  - 0730-2312 (Linking)
VI  - 124
IP  - 5
DP  - 2023 May
TI  - An antibody that targets cell-surface glucose-regulated protein-78 inhibits 
      expression of inflammatory cytokines and plasminogen activator inhibitors by 
      macrophages.
PG  - 743-752
LID - 10.1002/jcb.30401 [doi]
AB  - 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 alpha(2) -macroglobulin (alpha(2) M) and tissue-type plasminogen 
      activator (tPA). In macrophages, alpha(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 
      NFkappaB 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, alpha(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.
CI  - (c) 2023 Wiley Periodicals LLC.
FAU - Gunner, Cory B
AU  - Gunner CB
AD  - Department of Pathology, University of San Diego California School of Medicine, 
      La Jolla, California, USA.
FAU - Azmoon, Pardis
AU  - Azmoon P
AD  - Department of Pathology, University of San Diego California School of Medicine, 
      La Jolla, California, USA.
FAU - Mantuano, Elisabetta
AU  - Mantuano E
AD  - Department of Pathology, University of San Diego California School of Medicine, 
      La Jolla, California, USA.
FAU - Das, Lipsa
AU  - Das L
AD  - Department of Cellular and Molecular Medicine, University of Arizona Cancer 
      Center, Tucson, Arizona, USA.
FAU - Zampieri, Carlotta
AU  - Zampieri C
AD  - Department of Pathology, University of San Diego California School of Medicine, 
      La Jolla, California, USA.
FAU - Pizzo, Salvatore V
AU  - Pizzo SV
AD  - Department of Pathology, Duke University Medical Center, Durham, North Carolina, 
      USA.
FAU - Gonias, Steven L
AU  - Gonias SL
AUID- ORCID: 0000-0003-0843-4607
AD  - Department of Pathology, University of San Diego California School of Medicine, 
      La Jolla, California, USA.
LA  - eng
GR  - R01 HL136395/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20230322
PL  - United States
TA  - J Cell Biochem
JT  - Journal of cellular biochemistry
JID - 8205768
RN  - 0 (Cytokines)
RN  - 0 (Membrane Proteins)
RN  - 0 (Plasminogen Inactivators)
RN  - 0 (Endoplasmic Reticulum Chaperone BiP)
RN  - 6384-92-5 (N-Methylaspartate)
RN  - 0 (Antibodies)
RN  - 0 (Low Density Lipoprotein Receptor-Related Protein-1)
SB  - IM
MH  - Humans
MH  - *Cytokines/metabolism
MH  - Membrane Proteins/metabolism
MH  - Plasminogen Inactivators/metabolism
MH  - *Diabetes Mellitus, Type 2/metabolism
MH  - Endoplasmic Reticulum Chaperone BiP
MH  - N-Methylaspartate/metabolism
MH  - Macrophages/metabolism
MH  - Antibodies
MH  - Low Density Lipoprotein Receptor-Related Protein-1/genetics/metabolism
PMC - PMC10200756
MID - NIHMS1883810
OTO - NOTNLM
OT  - LRP1
OT  - NMDA receptor
OT  - PAI1
OT  - PAI2
OT  - glucose-regulated protein-78
OT  - tissue-type plasminogen activator
OT  - alpha2-macroglobulin
COIS- Conflict of Interest The authors declare no conflict of interest.
EDAT- 2023/03/23 06:00
MHDA- 2023/05/22 06:42
PMCR- 2024/05/01
CRDT- 2023/03/22 15:32
PHST- 2023/03/02 00:00 [revised]
PHST- 2023/01/13 00:00 [received]
PHST- 2023/03/12 00:00 [accepted]
PHST- 2023/05/22 06:42 [medline]
PHST- 2023/03/23 06:00 [pubmed]
PHST- 2023/03/22 15:32 [entrez]
PHST- 2024/05/01 00:00 [pmc-release]
AID - 10.1002/jcb.30401 [doi]
PST - ppublish
SO  - J Cell Biochem. 2023 May;124(5):743-752. doi: 10.1002/jcb.30401. Epub 2023 Mar 
      22.