Epigenetic Silencing of RIPK3 in Hepatocytes Prevents MLKL-mediated Necroptosis From Contributing to Liver Pathologies

Preston, Simon; Stutz, Michael D.; Allison, Cody; Nachbur, Ueli; Gouil, Quentin; Tran, Bang Manh; Duvivier, Valérie; Arandjelovic, Philip; Cooney, James P.; Mackiewicz, Liana; Meng, Yanxiang; Schaefer, Jan; Bader, Stefanie; Peng, Huamin; Valaydon, Zina; Rajasekaran, Pravin; Jennison, Charlie; Lopaticki, Sash; Farrell, Ann; Howell, Jess; Croagh, Catherine; Karunakaran, Denuja; Schuster-Klein, Carole; Murphy, James M.; Fifis, Theodora; Christophi, Christopher; Vincan, Elizabeth; Blewitt, Marnie E.; Thompson, Alexander; Boddey, Justin A; Doerflinger, Marcel; Pellegrini, Marc

doi:10.1053/j.gastro.2022.08.040

Cited by 42 publications

(40 citation statements)

References 57 publications

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“…Two recent reports deserve comment. First, an interesting study suggested that hepatocytes have an epigenetic mechanism to prevent the expression of RIP3 ( 52 ). However, using the techniques described in Materials and Methods, we, like others ( 18 – 20 , 22 – 25 ), were able to show expression of RIP3 and p-MLKL in human and mouse NASH liver, and we documented specific expression in hepatocytes ( 18 ).…”

Section: Discussionmentioning

confidence: 99%

CD47-SIRPα axis blockade in NASH promotes necroptotic hepatocyte clearance by liver macrophages and decreases hepatic fibrosis

Shi

Wang

et al. 2022

Sci. Transl. Med.

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Necroptosis contributes to hepatocyte death in nonalcoholic steatohepatitis (NASH), but the fate and roles of necroptotic hepatocytes (necHCs) in NASH remain unknown. We show here that the accumulation of necHCs in human and mouse NASH liver is associated with an up-regulation of the “don’t-eat-me” ligand CD47 on necHCs, but not on apoptotic hepatocytes, and an increase in the CD47 receptor SIRPα on liver macrophages, consistent with impaired macrophage-mediated clearance of necHCs. In vitro, necHC clearance by primary liver macrophages was enhanced by treatment with either anti-CD47 or anti-SIRPα. In a proof-of-concept mouse model of inducible hepatocyte necroptosis, anti-CD47 antibody treatment increased necHC uptake by liver macrophages and inhibited markers of hepatic stellate cell (HSC) activation, which is responsible for liver fibrogenesis. Treatment of two mouse models of diet-induced NASH with anti-CD47, anti-SIRPα, or AAV8-H1-shCD47 to silence CD47 in hepatocytes increased the uptake of necHC by liver macrophages and decreased markers of HSC activation and liver fibrosis. Anti-SIRPα treatment avoided the adverse effect of anemia found in anti-CD47–treated mice. These findings provide evidence that impaired clearance of necHCs by liver macrophages due to CD47-SIRPα up-regulation contributes to fibrotic NASH, and suggest therapeutic blockade of the CD47-SIRPα axis as a strategy to decrease the accumulation of necHCs in NASH liver and dampen the progression of hepatic fibrosis.

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Section: Discussionmentioning

confidence: 99%

CD47-SIRPα axis blockade in NASH promotes necroptotic hepatocyte clearance by liver macrophages and decreases hepatic fibrosis

Shi

Wang

et al. 2022

Sci. Transl. Med.

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“…Of note, unlike MLKL, RIPK3 is not ubiquitously expressed. Cumulative evidence supports that RIPK3 protein and transcripts are not detectable in some types of primary tumors and cancer cell lines, which has been attributed to the hyper-methylation of the promoter region of RIPK3 12 , 28 – 30 . A very recent work 12 and our data (Fig.…”

Section: Discussionmentioning

confidence: 98%

“…Cumulative evidence supports that RIPK3 protein and transcripts are not detectable in some types of primary tumors and cancer cell lines, which has been attributed to the hyper-methylation of the promoter region of RIPK3 12 , 28 – 30 . A very recent work 12 and our data (Fig. 1 ) further show that RIPK3-silenced cell context, such as HCC cells, generates a widely-existing situation with deficiency in necroptotic signaling.…”

Section: Discussionmentioning

confidence: 98%

“…For example, MLKL is involved in endosomal trafficking and generation of extracellular vesicles, which appears independent of RIPK3 but this role could be enhanced by RIPK3 32 . In this study, we pay attention to HCCs that are characterized by intrinsic silencing of RIPK3 12 . This context allowed us to reveal a previously unrecognized role of MLKL in circumventing parthanatos to maintain the survival of HCC cells in a high-fat microenvironment in the liver.…”

Section: Discussionmentioning

confidence: 99%

“…Blockage of RIPK3-mediated necroptosis ameliorates liver injury and fibrosis 8 – 11 . On the other hand, it is increasingly noted that RIPK3 is epigenetically silenced in primary hepatocytes in multiple liver disease models and prevents MLKL-mediated cell necroptosis 5 , 12 , 13 .…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A RIPK3-independent role of MLKL in suppressing parthanatos promotes immune evasion in hepatocellular carcinoma

et al. 2023

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Mixed lineage kinase domain-like (MLKL) is widely accepted as an executioner of necroptosis, in which MLKL mediates necroptotic signaling and triggers cell death in a receptor-interacting protein kinase 3 (RIPK3)-dependent manner. Recently, it is increasingly noted that RIPK3 is intrinsically silenced in hepatocytes, raising a question about the role of MLKL in hepatocellular carcinoma (HCC). This study reports a previously unrecognized role of MLKL in regulating parthanatos, a programmed cell death distinct from necroptosis. In HCC cells with intrinsic RIPK3 deficiency, knockout of MLKL impedes the orthotopic tumor growth, activates the anti-tumor immune response and enhances the therapeutic effect of immune checkpoint blockade in syngeneic HCC tumor models. Mechanistically, MLKL is required for maintaining the endoplasmic reticulum (ER)-mitochondrial Mg2+ dynamics in HCC cells. MLKL deficiency restricts ER Mg2+ release and mitochondrial Mg2+ uptake, leading to ER dysfunction and mitochondrial oxidative stress, which together confer increased susceptibility to metabolic stress-induced parthanatos. Importantly, pharmacological inhibition of poly(ADP-ribose) polymerase to block parthanatos restores the tumor growth and immune evasion in MLKL-knockout HCC tumors. Together, our data demonstrate a new RIPK3-independent role of MLKL in regulating parthanatos and highlight the role of MLKL in facilitating immune evasion in HCC.

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Improvement of Therapeutic Effect via Inducing Non‐Apoptotic Cell Death Using mRNA‐Protection Nanocage

Kim,

Kim

et al. 2024

Adv Healthcare Materials

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Necroptosis, a cell death mechanism with the characteristics of both apoptosis and necrosis, is proposed as a promising therapeutic approach for cancer therapy. Induction of necroptosis for cancer therapy may be possible through the regulation of the expression of a key factor gene receptor‐interacting protein kinase‐3 (RIPK3) via in vitro transcription (IVT) mRNA delivery. However, mRNA is susceptible to degradation and has a low delivery efficiency, which highlights the requirement of a proper delivery vehicle for intracellular delivery. Therefore, a new mRNA delivery system based on the nanostructured silica nanoparticles, termed mRNA‐protective nanocage (mPN) has been developed. High‐efficiency expression of RIPK3 and induction of necroptosis is achieved through delivery of RIPK3 IVT mRNA with mPN in vitro and in vivo models. Importantly, the mPN carrying RIPK3 mRNA distributed locally in tumors upon intravascular injection, and successfully induced necroptosis and immune cell infiltration, a hallmark of necroptosis. the suppression of tumor growth in a murine cancer model, demonstrating the synergistic effect of RIPK3 mRNA‐ and immune cell‐mediated therapy is also observed. These findings suggest the potential for anticancer therapy through necroptosis induction and provide a strategy for the development of mRNA‐based nanomedicine.

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Epigenetic Silencing of RIPK3 in Hepatocytes Prevents MLKL-mediated Necroptosis From Contributing to Liver Pathologies

Cited by 42 publications

References 57 publications

CD47-SIRPα axis blockade in NASH promotes necroptotic hepatocyte clearance by liver macrophages and decreases hepatic fibrosis

CD47-SIRPα axis blockade in NASH promotes necroptotic hepatocyte clearance by liver macrophages and decreases hepatic fibrosis

A RIPK3-independent role of MLKL in suppressing parthanatos promotes immune evasion in hepatocellular carcinoma

Improvement of Therapeutic Effect via Inducing Non‐Apoptotic Cell Death Using mRNA‐Protection Nanocage

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