Regulation of NKT cell-mediated immune responses to tumours and liver inflammation by mitochondrial PGAM5-Drp1 signalling

Abstract

The receptor-interacting protein kinase 3 (RIPK3) plays crucial roles in programmed necrosis and innate inflammatory responses. However, a little is known about the involvement of RIPK3 in NKT cell-mediated immune responses. Here, we demonstrate that RIPK3 plays an essential role in NKT cell function via activation of the mitochondrial phosphatase phosphoglycerate mutase 5 (PGAM5). RIPK3-mediated activation of PGAM5 promotes the expression of cytokines by facilitating nuclear translocation of NFAT and dephosphorylation of dynamin-related protein 1 (Drp1), a GTPase is essential for mitochondrial homoeostasis. Ripk3−/− mice show reduced NKT cell responses to metastatic tumour cells, and both deletion of RIPK3 and pharmacological inhibition of Drp1 protects mice from NKT cell-mediated induction of acute liver damage. Collectively, the results identify a crucial role for RIPK3-PGAM5-Drp1/NFAT signalling in NKT cell activation, and further suggest that RIPK3-PGAM5 signalling may mediate crosstalk between mitochondrial function and immune signalling.

The pseudokinase MLKL mediates programmed hepatocellular necrosis independently of RIPK3 during hepatitis

“…Consistently, Ripk3 -/-mice developed ConA-induced hepatitis as severe as control mice. Accordingly, we observed only low basal levels of RIPK3 in hepatocytes, and similar to other reports (19,43), RIPK3 positivity was rather limited to nonparenchymal cells, particularly Kupffer cells. Although we have previously shown that RIPK3 is upregulated in intestinal epithelial cells undergoing TNF-α-triggered necroptosis (8), we were unable to detect induction of RIPK3 mRNA or protein in hepatocytes during the course of experimentally induced hepatitis or in human AIH.…”

“…Although we have previously shown that RIPK3 is upregulated in intestinal epithelial cells undergoing TNF-α-triggered necroptosis (8), we were unable to detect induction of RIPK3 mRNA or protein in hepatocytes during the course of experimentally induced hepatitis or in human AIH. In line with this, a recent study demonstrated that RIPK3 expression in hepatocytes is dispensable for inflammatory liver injury (43).…”

“…For the first time to our knowledge, we describe that IFN-γ signal transduction in hepatocytes, via activation of STAT1 and transactivation of the Mlkl promoter, rapidly increased the amount of MLKL transcripts and protein, which are low under steady-state conditions. PMHs display spontaneous cell death during long-term cell culture but show rather low sensitivity to necroptosis induction by TNF-α/zVAD/SMAC mimetic treatment (43,48). However, pretreatment of mice or cells with IFN-γ upregulated Mlkl in hepatocytes and increased their susceptibility toward cell death (Supplemental Figure 12).…”

The mitochondrial dynamics in cancer and immune-surveillance

“…Additionally, receptor-interacting protein kinase -1 and -3 (RIPK1/3)-dependent and lipopolysaccharide (LPS)-dependent inflammasome activation, and cytokine production upon viral infection, requires Drp1-dependent mitochondrial fission to induce mitochondrial damage and generate ROS [186,187]. The mitochondrial phosphatase phosphoglycerate mutase 5 (PGAM5) is the mediator of such RIPK-dependent Drp1 activation [188]. Similarly, microglial cells (MCs) in the central nervous system require Drp1-driven mitochondrial fragmentation and ROS signalling for correct cytokine production [189] ( Fig.…”

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

“…showed that deletion of Ripk3 in myeloid cells, but not hepatocytes, protected mice against ConA toxicity (20). Some of the discrepancies among these reports may be due to off-target effects of inhibitors, the dose of inhibitors and ConA used, strain-specific variations in the mice, and inconsistency in the use of littermate controls.…”