A murder mystery in the liver: who done it and how?
Lily Dara, … , Zhang-Xu Liu, Neil Kaplowitz
Lily Dara, … , Zhang-Xu Liu, Neil Kaplowitz
Published October 17, 2016
Citation Information: J Clin Invest. 2016;126(11):4068-4071. https://doi.org/10.1172/JCI90830.
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Commentary

A murder mystery in the liver: who done it and how?

Abstract

Hepatocyte death, which can be apoptosis or necrosis depending on the context, is a prominent feature of liver disease. The lectin concanavalin A (ConA) activates immune cells, resulting in inflammatory liver injury and hepatocyte necrosis. In this issue of the JCI, Günther et al. demonstrate that the pseudokinase mixed lineage kinase domain–like protein (MLKL) participates in hepatocyte death in ConA injury and that MLKL-mediated death is independent of the receptor-interacting protein kinase RIPK3. RIPK3 was absent in hepatocytes, and MLKL-deficient mice, but not RIPK3-deficient mice, were protected from ConA-induced liver injury. The authors also present evidence that an unidentified kinase activates MLKL, as RIPK1 bound MLKL but did not phosphorylate it. Moreover, ConA rapidly induced MLKL, mediated by the IFN-γ/STAT1 pathway, while activation and translocation to the plasma membrane required TNF. Increased phospho-MLKL staining in liver biopsies from patients with autoimmune hepatitis suggests a role for MLKL in this disease. This study describes a previously unrecognized form of cell death in the liver that should be further explored as a potential therapeutic target in immune-mediated liver injury.

Authors

Lily Dara, Zhang-Xu Liu, Neil Kaplowitz

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Figure 1

ConA-induced liver necrosis.

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ConA-induced liver necrosis. ConA activates T cells and NKT cells, which...
ConA activates T cells and NKT cells, which secrete cytokines, such as IFN-γ and TNF, that are known to be critical for liver injury in this model. Günther et al. discovered that IFN-γ signaling induces MLKL above a critical threshold (13). This increase in MLKL sensitizes hepatocytes to necrosis but alone is insufficient to promote necrosis and requires activation of MLKL. RIPK3 is the only kinase known to activate MLKL; however, RIPK3 is not expressed in hepatocytes or induced by ConA. Ripk3–/– mice given ConA developed liver injury, but Mlkl–/– mice were resistant to ConA. The RIPK1 inhibitor nec-1s was protective in ConA-treated mice, and this protection was upstream of MLKL activation. RIPK1 expression increased in this model and was independent of TNF or IFN-γ, occurring via an unknown mechanism. RIPK1 was found in a complex with MLKL, presumably with other not-yet-identified proteins; however, RIPK1 did not directly phosphorylate MLKL but possibly leads to the activation of the unidentified kinase activator of MLKL. As TNF signaling is required for cell death, it must lead to the activation of either RIPK1 or the unidentified kinase to activate MLKL. IFN-γR, IFN-γ receptor; TNFR, TNF receptor.