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MLKL-mediated hepatocyte necrosis in immune liver disease—not all hepatocyte death is the same

▸ Gunther C, He GW, Kremer AE, et al. The pseudokinase MLKL mediates programmed hepatocellular necrosis independently of RIPK3 during hepatitis. J Clin Invest 2016;126:4346–60.

Hepatocellular death has long been associated with both acute and chronic liver injury. Mechanisms of cell death can extend beyond apoptosis and necrosis and vary greatly, with pathways such as necroptosis (programmed cell necrosis) now well described. A more detailed dissection of the pathways involved in hepatocellular death in different modes of liver injury may yield new insights into disease pathogenesis. In this article, the authors describe a novel mixed lineage kinase domain-like protein (MLKL)-dependent programmed hepatocyte necrosis pathway, which may have relevance for the pathogenesis of immune-mediated liver diseases. In the context of necroptosis, receptor interacting protein kinase 3 (RIPK3) results in the activation of MLKL, which has been shown to cause membrane disintegration. Assessment of liver tissue from patients with distinct liver diseases demonstrated a strong upregulation in MLKL expression from patients with autoimmune hepatitis, with activated MLKL localising to hepatocyte cell membranes from areas of hepatocellular death. Similarly, in a murine model of immune-mediated liver injury, concanavalin A (ConA) treatment resulted in the upregulation of MLKL, which localised to hepatocytes in areas of necrosis. MLKL-deficient mice showed a striking protection from ConA-induced hepatocellular necrosis, while MLKL deficiency did not have any effect on liver injury in either the acetaminophen or LPS/D-galactosamine murine models. These data suggest that the mode of hepatocyte death is critically dependent on the mode of injury. The authors then dissected the mechanism of MLKL activation in the ConA model, and surprisingly discovered that it was not RIPK3 dependent but seemed to rely on functional RIPK1. This suggests that hepatocyte death in immune-mediated liver disease may not be mediated via the currently described necroptosis pathway. However, IFN-γ production …

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