Abstract
The phosphatidylserine receptor (PSR) recognizes a surface marker on apoptotic cells and initiates engulfment. This receptor is important for effective apoptotic cell clearance and maintains normal tissue homeostasis and regulation of the immune response. However, the regulation of PSR expression remains poorly understood. In this study, we determined that interferon regulatory factor-1 (IRF-1) was dramatically upregulated upon viral infection in the fish cell. We observed apoptosis in virus-infected cells and found that both PSR and IRF-1 increased simultaneously. Based on a bioinformatics promoter assay, IRF-1 binding sites were identified in the PSR promoter. Compared to normal viral infection, we found that PSR expression was delayed, viral replication was increased and virus-induced apoptosis was inhibited following IRF-1 suppression with morpholino oligonucleotides. A luciferase assay to analyze promoter activity revealed a decreasing trend after the deletion of the IRF-1 binding site on PSR promoter. The results of this study indicated that infectious pancreatic necrosis virus (IPNV) infection induced both the apoptotic and interferon (IFN) pathways, and IRF-1 was involved in regulating PSR expression to induce anti-viral effects. Therefore, this work suggests that PSR expression in salmonid cells during IPNV infection is activated when IRF-1 binds the PSR promoter. This is the first report to show the potential role of IRF-1 in triggering the induction of apoptotic cell clearance-related genes during viral infection and demonstrates the extensive crosstalk between the apoptotic and innate immune response pathways.
Highlights
The phosphatidylserine receptor (PSR) plays an important role in the clearance of apoptotic cells by recognizing phosphatidylserine (PS or PtdSer) on apoptotic cells and subsequently engulfing them.The PSR is the major receptor involved in apoptotic cell clearance during development [1] and is associated with the phagocytosis of apoptotic cells in chronic pancreatitis [2]
Our results suggested that infectious pancreatic necrosis virus (IPNV) infection induced both the apoptosis and the IFN pathways, and in particular interferon regulatory factor-1 (IRF-1), which is involved in the latter pathway and is a regulator of PSR production that can exert anti-viral effects by promoting apoptotic cell clearance
During viral infection, and apoptosis precedes and subsequently promotes PSR expression. This is the first study to demonstrate the relationship between the apoptosis-related gene PSR and the immune-related transcription factor IFN regulatory factors (IRFs)-1, which exhibits a novel mechanism for PSR induction
Summary
The phosphatidylserine receptor (PSR) plays an important role in the clearance of apoptotic cells by recognizing phosphatidylserine (PS or PtdSer) on apoptotic cells and subsequently engulfing them. Based on our previous studies, infectious pancreatic necrosis virus (IPNV) infection can induce apoptosis through activating caspase-3, -8, -9 in salmonid and zebrafish cell lines, and apoptotic cells are engulfed by neighboring cells [12,13,14]. Our results suggested that IPNV infection induced both the apoptosis and the IFN pathways, and in particular IRF-1, which is involved in the latter pathway and is a regulator of PSR production that can exert anti-viral effects by promoting apoptotic cell clearance. We explored for the first time the potential role of IRFs in triggering the induction of PSR, an apoptotic cell clearance-associated gene, during viral infection, emphasizing the relevance of the relationship between apoptosis and the immune system
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