MFG-E8 Maintains Cellular Homeostasis by Suppressing Endoplasmic Reticulum Stress in Pancreatic Exocrine Acinar Cells

Abstract

Excessive endoplasmic reticulum (ER) stress contributes significantly to the pathogenesis of exocrine acinar damage in acute pancreatitis. Our previous study found that milk fat globule EGF factor 8 (MFG-E8), a lipophilic glycoprotein, alleviates acinar cell damage during AP via binding to αvβ3/5 integrins. Ligand-dependent integrin-FAK activation of STAT3 was reported to be of great importance for maintaining cellular homeostasis. However, MFG-E8’s role in ER stress in pancreatic exocrine acinar cells has not been evaluated. To study this, thapsigargin, brefeldin A, tunicamycin and cerulein + LPS were used to induce ER stress in rat pancreatic acinar cells in vitro. L-arginine- and cerulein + LPS-induced acute pancreatitis in mice were used to study ER stress in vivo. The results showed that MFG-E8 dose-dependently inhibited ER stress under both in vitro and in vivo conditions. MFG-E8 knockout mice suffered more severe ER stress and greater inflammatory response after L-arginine administration. Mechanistically, MFG-E8 increased phosphorylation of FAK and STAT3 in cerulein + LPS-treated pancreatic acinar cells. The presence of specific inhibitors of αvβ3/5 integrin, FAK or STAT3 abolished MFG-E8’s effect on cerulein + LPS-induced ER stress in pancreatic acinar cells. In conclusion, MFG-E8 maintains cellular homeostasis by alleviating ER stress in pancreatic exocrine acinar cells.

Milk fat globule epidermal growth factor 8 alleviates liver injury in severe acute pancreatitis by restoring autophagy flux and inhibiting ferroptosis in hepatocytes

“…MFG-E8 is involved in a variety of intercellular signaling pathways and enhances the phagocytosis of inflammatory cells and apoptotic cells by macrophages[ 24 - 26 ]. Our previous study confirmed that MFG-E8 maintains cellular homeostasis by suppressing endoplasmic reticulum stress (ERS) in pancreatic exocrine acinar cells and protects against SAP[ 27 , 28 ]. ERS has been reported to play an important role in promoting intracellular autophagy disorder and inducing ferroptosis[ 29 ].…”

“…Our previous studies have shown that MFG-E8 maintains cellular homeostasis by alleviating ER stress in pancreatic exocrine acinar cells. The beneficial effects of MFG-E8 are mediated through activating the αVβ3/5 integrin-FAK-STAT3 signaling pathway[ 28 ]. The present study also explored the potential role of the αVβ3/5 integrin-FAK-STAT3 signaling pathway in the liver.…”

Targeting MFGE8 secreted by cancer-associated fibroblasts blocks angiogenesis and metastasis in esophageal squamous cell carcinoma

“…For example, MFGE8-blocking antibody reduces phagocytic and macrophage activity ( 34 ). In acute pancreatitis, the effect of MFGE8 could be abrogated by cilengitide, a selective integrin αVβ3/αVβ5 inhibitor ( 35 ). In the current investigation, the interaction between MFGE8 and integrin αVβ3/αVβ5 was disrupted through the application of neutralizing antibodies, and their impact was assessed via in vitro and in vivo experimentation.…”