The Protective Role of Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Protein Sigma-1 Receptor in Regulating Endothelial Inflammation and Permeability Associated with Acute Lung Injury
Earlier studies from our lab identified endoplasmic reticulum (ER) chaperone BiP/GRP78, an important component of MAM, to be a novel determinant of endothelial cell (EC) dysfunction associated with acute lung injury (ALI). Sigma1R (Sig1R) is another unique ER receptor chaperone that has been identif...
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| Format: | Article |
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MDPI AG
2023-12-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/13/1/5 |
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| author | Zahra Mahamed Mohammad Shadab Rauf Ahmad Najar Michelle Warren Millar Jashandeep Bal Traci Pressley Fabeha Fazal |
| author_facet | Zahra Mahamed Mohammad Shadab Rauf Ahmad Najar Michelle Warren Millar Jashandeep Bal Traci Pressley Fabeha Fazal |
| author_sort | Zahra Mahamed |
| collection | DOAJ |
| description | Earlier studies from our lab identified endoplasmic reticulum (ER) chaperone BiP/GRP78, an important component of MAM, to be a novel determinant of endothelial cell (EC) dysfunction associated with acute lung injury (ALI). Sigma1R (Sig1R) is another unique ER receptor chaperone that has been identified to associate with BiP/GRP78 at the MAM and is known to be a pluripotent modulator of cellular homeostasis. However, it is unclear if Sig1R also plays a role in regulating the EC inflammation and permeability associated with ALI. Our data using human pulmonary artery endothelial cells (HPAECs) showed that siRNA-mediated knockdown of Sig1R potentiated LPS-induced the expression of proinflammatory molecules ICAM-1, VCAM-1 and IL-8. Consistent with this, Sig1R agonist, PRE-084, known to activate Sig1R by inducing its dissociation from BiP/GRP78, blunted the above response. Notably, PRE-084 failed to blunt LPS-induced inflammatory responses in Sig1R-depleted cells, confirming that the effect of PRE-084 is driven by Sig1R. Furthermore, Sig1R antagonist, NE-100, known to inactivate Sig1R by blocking its dissociation from BiP/GRP78, failed to block LPS-induced inflammatory responses, establishing that dissociation from BiP/GRP78 is required for Sig1R to exert its anti-inflammatory action. Unlike Sig1R, the siRNA-mediated knockdown or Subtilase AB-mediated inactivation of BiP/GRP78 protected against LPS-induced EC inflammation. Interestingly, the protective effect of BiP/GRP78 knockdown or inactivation was abolished in cells that were depleted of Sig1R, confirming that BiP/GRP78 knockdown/inactivation-mediated suppression of EC inflammation is mediated via Sig1R. In view of these findings, we determined the in vivo relevance of Sig1R in a mouse model of sepsis-induced ALI. The intraperitoneal injection of PRE-084 mitigated sepsis-induced ALI, as evidenced by a decrease in ICAM-1, IL-6 levels, lung PMN infiltration, and lung vascular leakage. Together, these data evidence a protective role of Sig1R against endothelial dysfunction associated with ALI and identify it as a viable target in terms of controlling ALI in sepsis. |
| first_indexed | 2024-03-08T15:10:23Z |
| format | Article |
| id | doaj.art-5eea64e8ec274c6799b5505a1a377922 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-08T15:10:23Z |
| publishDate | 2023-12-01 |
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| series | Cells |
| spelling | doaj.art-5eea64e8ec274c6799b5505a1a3779222024-01-10T14:53:09ZengMDPI AGCells2073-44092023-12-01131510.3390/cells13010005The Protective Role of Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Protein Sigma-1 Receptor in Regulating Endothelial Inflammation and Permeability Associated with Acute Lung InjuryZahra Mahamed0Mohammad Shadab1Rauf Ahmad Najar2Michelle Warren Millar3Jashandeep Bal4Traci Pressley5Fabeha Fazal6Department of Pediatrics (Neonatology), Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USADepartment of Pediatrics (Neonatology), Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USADepartment of Pediatrics (Neonatology), Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USADepartment of Pediatrics (Neonatology), Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USADepartment of Pediatrics (Neonatology), Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USADepartment of Pediatrics (Neonatology), Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USADepartment of Pediatrics (Neonatology), Lung Biology and Disease Program, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USAEarlier studies from our lab identified endoplasmic reticulum (ER) chaperone BiP/GRP78, an important component of MAM, to be a novel determinant of endothelial cell (EC) dysfunction associated with acute lung injury (ALI). Sigma1R (Sig1R) is another unique ER receptor chaperone that has been identified to associate with BiP/GRP78 at the MAM and is known to be a pluripotent modulator of cellular homeostasis. However, it is unclear if Sig1R also plays a role in regulating the EC inflammation and permeability associated with ALI. Our data using human pulmonary artery endothelial cells (HPAECs) showed that siRNA-mediated knockdown of Sig1R potentiated LPS-induced the expression of proinflammatory molecules ICAM-1, VCAM-1 and IL-8. Consistent with this, Sig1R agonist, PRE-084, known to activate Sig1R by inducing its dissociation from BiP/GRP78, blunted the above response. Notably, PRE-084 failed to blunt LPS-induced inflammatory responses in Sig1R-depleted cells, confirming that the effect of PRE-084 is driven by Sig1R. Furthermore, Sig1R antagonist, NE-100, known to inactivate Sig1R by blocking its dissociation from BiP/GRP78, failed to block LPS-induced inflammatory responses, establishing that dissociation from BiP/GRP78 is required for Sig1R to exert its anti-inflammatory action. Unlike Sig1R, the siRNA-mediated knockdown or Subtilase AB-mediated inactivation of BiP/GRP78 protected against LPS-induced EC inflammation. Interestingly, the protective effect of BiP/GRP78 knockdown or inactivation was abolished in cells that were depleted of Sig1R, confirming that BiP/GRP78 knockdown/inactivation-mediated suppression of EC inflammation is mediated via Sig1R. In view of these findings, we determined the in vivo relevance of Sig1R in a mouse model of sepsis-induced ALI. The intraperitoneal injection of PRE-084 mitigated sepsis-induced ALI, as evidenced by a decrease in ICAM-1, IL-6 levels, lung PMN infiltration, and lung vascular leakage. Together, these data evidence a protective role of Sig1R against endothelial dysfunction associated with ALI and identify it as a viable target in terms of controlling ALI in sepsis.https://www.mdpi.com/2073-4409/13/1/5sigma 1 receptorendothelial cellsmitochondria-associated endoplasmic reticulum membranesinflammationpermeabilityacute lung injury |
| spellingShingle | Zahra Mahamed Mohammad Shadab Rauf Ahmad Najar Michelle Warren Millar Jashandeep Bal Traci Pressley Fabeha Fazal The Protective Role of Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Protein Sigma-1 Receptor in Regulating Endothelial Inflammation and Permeability Associated with Acute Lung Injury Cells sigma 1 receptor endothelial cells mitochondria-associated endoplasmic reticulum membranes inflammation permeability acute lung injury |
| title | The Protective Role of Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Protein Sigma-1 Receptor in Regulating Endothelial Inflammation and Permeability Associated with Acute Lung Injury |
| title_full | The Protective Role of Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Protein Sigma-1 Receptor in Regulating Endothelial Inflammation and Permeability Associated with Acute Lung Injury |
| title_fullStr | The Protective Role of Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Protein Sigma-1 Receptor in Regulating Endothelial Inflammation and Permeability Associated with Acute Lung Injury |
| title_full_unstemmed | The Protective Role of Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Protein Sigma-1 Receptor in Regulating Endothelial Inflammation and Permeability Associated with Acute Lung Injury |
| title_short | The Protective Role of Mitochondria-Associated Endoplasmic Reticulum Membrane (MAM) Protein Sigma-1 Receptor in Regulating Endothelial Inflammation and Permeability Associated with Acute Lung Injury |
| title_sort | protective role of mitochondria associated endoplasmic reticulum membrane mam protein sigma 1 receptor in regulating endothelial inflammation and permeability associated with acute lung injury |
| topic | sigma 1 receptor endothelial cells mitochondria-associated endoplasmic reticulum membranes inflammation permeability acute lung injury |
| url | https://www.mdpi.com/2073-4409/13/1/5 |
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