Abstract
Ischemia-reperfusion (I/R) is a major reason of hepatocyte injury during liver surgery and transplantation. Myeloid cells including macrophages and neutrophils play important roles in sustained tissue inflammation and damage, but the mechanisms regulating myeloid cells activity have been elusive. In this study, we investigate the role of Notch signaling in myeloid cells during hepatic I/R injury by using a mouse model of myeloid specific conditional knockout of RBP-J. Myeloid-specific RBP-J deletion alleviated hepatic I/R injury. RBP-J deletion in myeloid cells decreased hepatocytes apoptosis after hepatic I/R injury. Furthermore, myeloid-specific RBP-J deletion led to attenuated inflammation response in liver after I/R injury. Consistently, Notch blockade reduced the production of inflammatory cytokines by macrophages in vitro. We also found that blocking Notch signaling reduced NF-κB activation and increased cylindromatosis (CYLD) expression and knockdown of CYLD rescued reduction of inflammatory cytokines induced by Notch blockade in macrophages during I/R injury in vitro. On the other hand, activation of Notch signaling in macrophages led to increased inflammatory cytokine production and NF-κB activation and decreased CYLD expression in vitro. These data suggest that activation of Notch signaling in myeloid cells aggravates I/R injury, by enhancing the inflammation response by NF-κB through down regulation of CYLD.
Highlights
Warm ischemia reperfusion (I/R) injury of liver takes place under a number of clinical conditions, including hepatic resection surgery, liver transplantation, and hemorrhagic shock with fluid resuscitation[1]
To investigate the role of Notch signaling in myeloid cells that are critically involved in hepatic I/R injury, we employed myeloid-specific conditional knockout mice of RBP-J, the key DNA-binding protein mediating signaling from all four mammalian Notch receptors
These results suggested that conditional RBP-J deletion in myeloid cells did not influence the gross structure and function liver in mice
Summary
Warm ischemia reperfusion (I/R) injury of liver takes place under a number of clinical conditions, including hepatic resection surgery, liver transplantation, and hemorrhagic shock with fluid resuscitation[1]. Liver I/R injury involves a continuous process of inflammation and immune responses including the generation of danger-associated molecular patterns (DAMPs), activation of endothelial cells, recruitment and activation of immune cell populations, increased expression and release of adhesion molecules and cytokines, and over production of free radicals, resulting in hepatocyte death[2,3]. Established theory demonstrates that Kupffers’ cells are activated by oxidative stress in the initial phase of I/R injury and activated macrophages produce massive ROS and pro-inflammatory cytokines which can recruit neutrophils to the site of I/R-induced inflammation. Canonical Notch activation involves consecutive enzymatic receptor cleavages within the transmembrane domain executed by γsecretase-mediated reactions This process releases Notch intracellular domain (NICD) that subsequently translocates into the nucleus, where it interacts with the transcription factor C promoter-binding factor 1/recombination signal binding protein Jκ(RBP-J). Our results have demonstrated that blockade of Notch signaling by RBP-J deletion in myeloid cells alleviates hepatic I/R injury by compromised NF-κB activation through cylindromatosis (CYLD) up-regulation
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