ADAM8 Destroys the Endothelial Barrier and Promotes Leukocyte Extravasation to Aggravate Hepatic Ischemia-Reperfusion...

Hepatic ischemia-reperfusion injury (HIRI) is a local aseptic inflammatory response driven by innate immunity, and it can severely damage liver function. ADAM8 belongs to the ADAM (a disintegrin and metalloprotease domain) family and has been shown to be important in inflammation-related diseases. However, its role in HIRI remains unknown. ADAM8 expression was increased in the liver tissues of HIRI mice, which was also correlated with the progression of liver damage. Suppression of ADAM8 alleviated I/R-induced liver damage in mice, ameliorating hepatocyte injury and the release of inflammatory cytokines. ADAM8 knockdown upregulated the expression of CD31 and downregulated CD45 in liver tissues. In addition, ADAM8 knockdown downregulated Ly6G and citH3 double-positive cells in the liver tissue of HIRI mice, reducing the protein expression of citH3, indicating ADAM8 knockdown relieved neutrophil infiltration and the formation of neutrophil extracellular traps during HIRI. In OGD/R-treated C166 cells, ADAM8 was upregulated. ADAM8 knockdown inhibited endothelial cell permeability and neutrophil transmigration. Moreover, catalytic residue mutation of ADAM8 did not affect its protein expression but impaired the promotion of ADAM8 on endothelial cell permeability and neutrophil transmigration. BK-1361, an inhibitor of ADAM8, also attenuated endothelial cell permeability and neutrophil transmigration. Animal experiments confirmed that BK-1361 alleviates HIRI. These results suggested that the function of ADAM8 in disrupting the endothelial cell barrier and exacerbating leukocyte extravasation is dependent on its enzymatic activity. In summary, ADAM8 aggravates HIRI by disrupting the endothelial barrier, increasing endothelial permeability, accelerating leukocyte extravasation, and promoting the inflammatory response and hepatocyte injury.