RIPK1 protects from TNF-α-mediated liver damage during hepatitis

Abstract

Cell death of hepatocytes is a prominent characteristic in the pathogenesis of liver disease, while hepatolysis is a starting point of inflammation in hepatitis and loss of hepatic function. However, the precise molecular mechanisms of hepatocyte cell death, the role of the cytokines of hepatic microenvironment and the involvement of intracellular kinases, remain unclear. Tumor necrosis factor alpha (TNF-α) is a key cytokine involved in cell death or survival pathways and the role of RIPK1 has been associated to the TNF-α-dependent signaling pathway. We took advantage of two different deficient mouse lines, the RIPK1 kinase dead knock-in mice (Ripk1K45A) and the conditional knockout mice lacking RIPK1 only in liver parenchymal cells (Ripk1LPC-KO), to characterize the role of RIPK1 and TNF-α in hepatitis induced by concanavalin A (ConA). Our results show that RIPK1 is dispensable for liver homeostasis under steady-state conditions but in contrast, RIPK1 kinase activity contributes to caspase-independent cell death induction following ConA injection and RIPK1 also serves as a scaffold, protecting hepatocytes from massive apoptotic cell death in this model. In the Ripk1LPC-KO mice challenged with ConA, TNF-α triggers apoptosis, responsible for the observed severe hepatitis. Mechanism potentially involves both TNF-independent canonical NF-κB activation, as well as TNF-dependent, but canonical NF-κB-independent mechanisms. In conclusion, our results suggest that RIPK1 kinase activity is a pertinent therapeutic target to protect liver against excessive cell death in liver diseases.

Kinase-independent functions of RIPK1 regulate hepatocyte survival and liver carcinogenesis

“…We found that RIPK1 prevents endotoxin-induced liver damage by inhibiting TNFR1-induced hepatocyte death. These results are in agreement with recent reports showing that RIPK1-deficient hepatocytes were sensitive to TNF-induced death and that mice with LPC-specific Ripk1 knockout were highly susceptible to ConA-or LPS-induced liver damage (20)(21)(22)24). Our genetic studies showed that TNF induces hepatocyte death in RIPK1-deficient hepatocytes by activating TNFR1-TRADD-FADD-dependent apoptosis both in vivo and in vitro ( Figure 8A).…”

“…These results appear to be in contrast with the finding that knockdown or knockout of Ripk1 did not compromise TNF-induced NF-κB activation in hepatocytes (20,22,24). This discrepancy is most likely due to differences in the quantitative assessment of NF-κB signaling, as extensively discussed in previous studies on the role of RIPK1 in death of RIPK1-deficient hepatocytes is consistent with the model of 2 different pathways inducing apoptosis downstream of TNFR1, one that is RIPK1 dependent and one that is TRADD dependent (39).…”

“…LPC-KO mice were highly sensitive to concanavalin A-mediated (ConA-mediated) liver damage, which was partly induced by TNF-mediated hepatocyte apoptosis (24). Moreover, administration of LPS caused severe liver injury in RIPK1 LPC-KO mice by inducing TNF-dependent hepatocyte apoptosis (20,21).…”

“…Mice lacking RIPK1 specifically in LPCs (Ripk1 fl/fl Alfp-Cre mice, hereafter referred to as RIPK1 LPC-KO mice) did not develop spontaneous liver disease, showing that RIPK1 is not required for normal liver homeostasis under steady-state conditions (16,(20)(21)(22)(23)(24). However, RIPK1…”

SPATA2 regulates the activation of RIPK1 by modulating linear ubiquitination

“…Interestingly, the lethality of Spata2 −/− mice was still inhibited by Nec-1s, suggesting that cell death induced by the increased production of proinflammatory cytokines under Spata2-deficient conditions might still be RIPK1-dependent. Consistently, inhibition of RIPK1 pharmacologically and genetically also blocked the hepatitis induced by Con-A injection (Filliol et al 2016).…”