Abstract
During viral infections viruses express molecules that interfere with the host-cell death machinery and thus inhibit cell death responses. For example the viral FLIP (vFLIP) encoded by Kaposi’s sarcoma-associated herpesvirus interacts and inhibits the central cell death effector, Caspase-8. In order to analyze the impact of anti-apoptotic viral proteins, like vFlip, on liver physiology in vivo, mice expressing vFlip constitutively in hepatocytes (vFlipAlbCre+) were generated. Transgenic expression of vFlip caused severe liver tissue injury accompanied by massive hepatocellular necrosis and inflammation that finally culminated in early postnatal death of mice. On a molecular level, hepatocellular death was mediated by RIPK1-MLKL necroptosis driven by an autocrine TNF production. The loss of hepatocytes was accompanied by impaired bile acid production and disruption of the bile duct structure with impact on the liver-gut axis. Notably, embryonic development and tissue homeostasis were unaffected by vFlip expression. In summary our data uncovered that transgenic expression of vFlip can cause severe liver injury in mice, culminating in multiple organ insufficiency and death. These results demonstrate that viral cell death regulatory molecules exhibit different facets of activities beyond the inhibition of cell death that may merit more sophisticated in vitro and in vivo analysis.
Highlights
Viruses are involved in many pathogeneses of the human liver[1,2,3]
Since viral FLIP (vFLIP) has been described as a negative regulator of Caspase-8, we investigated whether liver injury as observed in vFlipAlbCre+ mice was caused by apoptosis or necrosis
Since TNF is known as main driver of necroptosis in the absence of caspase-8 activity, we investigated whether autocrine TNF production in vFlip expressing hepatocytes might trigger MLKL-dependent cell death
Summary
Viruses are involved in many pathogeneses of the human liver[1,2,3]. In order to defend the body from the invading pathogen, infected liver cells undergo programmed cell death to eliminate the pathogen followed by an recruitment of immune cells, resulting in acute liver damage and inflammation[4,5,6]. An persistent virusmediated inflammatory cell death response can result in chronic inflammation and potentially progression to hepatic fibrosis, cirrhosis, and oncogenesis[2,3,7]. A more profound understanding on the molecular mechanisms of programmed cell death in the context of liver diseases is crucial in order to identify prospective therapeutic targets[8,15]. Since the classical categorization in regulated apoptosis- and unregulated necrosis-mediated cell death has recently been challenged by the discovery of regulated necrosis[8]. Regulated necrosis exhibits the characteristic morphological hallmarks of necrosis, but describes several different forms of programmed cell death with distinct signaling pathways, such as necroptosis, pyroptosis, ferroptosis, and NETosis[8,9]
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