Abstract
The protein kinase RIPK1 plays a crucial role at the crossroad of stress-induced signaling pathways that affects cell’s decision to live or die. The present study aimed to define the role of RIPK1 in hepatocytes during fulminant viral hepatitis, a worldwide syndrome mainly observed in hepatitis B virus (HBV) infected patients. Mice deficient for RIPK1, specifically in liver parenchymal cells (Ripk1LPC-KO) and their wild-type littermates (Ripk1fl/fl), were challenged by either the murine hepatitis virus type 3 (MHV3) or poly I:C, a synthetic analog of double-stranded RNA mimicking viral pathogen-associated molecular pattern. Ripk1LPC-KO mice developed more severe symptoms at early stage of the MHV3-induced fulminant hepatitis. Similarly, administration of poly I:C only triggered increase of systemic transaminases in Ripk1LPC-KO mice, reflecting liver damage through induced apoptosis as illustrated by cleaved-caspase 3 labeling of liver tissue sections. Neutralization of TNF-α or prior depletion of macrophages were able to prevent the appearance of apoptosis of hepatocytes in poly I:C-challenged Ripk1LPC-KO mice. Moreover, poly I:C never induced direct hepatocyte death in primary culture whatever the murine genotype, while it always stimulated an anti-viral response. Our investigations demonstrated that RIPK1 protects hepatocytes from TNF-α secreted from macrophages during viral induced fulminant hepatitis. These data emphasize the potential worsening risks of an HBV infection in people with polymorphism or homozygous amorphic mutations already described for the RIPK1 gene.
Highlights
Fulminant viral hepatitis is a worldwide syndrome, which requires immediate intensive care, and is associated with massive hepatocyte death, hepatic encephalopathy, and multiple organ failure[1]
We investigate the unknown role of receptor interacting protein kinase-1 (RIPK1) during the specific circumstances of fulminant viral hepatitis
Histological observations of their liver did not reveal any anomaly. Animals from both groups were included in an experimental protocol for murine hepatitis virus type 3 (MHV3)-induced fulminant viral hepatitis
Summary
Fulminant viral hepatitis is a worldwide syndrome, which requires immediate intensive care, and is associated with massive hepatocyte death, hepatic encephalopathy, and multiple organ failure[1]. Even if non-hepatitis viruses, such as the herpes simplex virus (HSV) or the cytomegalovirus (CMV) are occasional etiological factors in immunocompromised patients, most fulminant hepatitis with an identifiable viral cause originates from infection (HBV) and more rarely the hepatitis A, C, or E viruses (HAV, HCV, HEV)[2,3]. The more physiologically relevant in vivo model to study fulminant viral hepatitis is MHV3 infection. This coronavirus is a single stranded, positive sense RNA virus. It is highly pathogenic and could cause death in 3–5 days depending on age, route of infection, viral doses, murine strain, and on the immune status of the animal[9].
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