Serum amyloid A3 is required for caerulein‐induced acute pancreatitis through induction of RIP3‐dependent necroptosis

Yang, Xinyi; R, Li; Xu, Lu; Qian, Feng; Sun, Lei

doi:10.1111/imcb.12382

Cited by 9 publications

(9 citation statements)

References 48 publications

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“…To analyze the clinical relevance of necroptotic mediators in liver transplantation and end-stage liver diseases, immunohistochemistry was performed on consecutive liver slices using validated RIPK3 18 , 19 and phosphorylated mixed lineage kinase domain-like (pMLKL) 20 , 21 antibodies. A cholangiocyte-specific cytokeratin-19 antibody was applied to localize bile ducts.…”

Section: Resultsmentioning

confidence: 99%

Recapitulating Cholangiopathy-Associated Necroptotic Cell Death In Vitro Using Human Cholangiocyte Organoids

Shi

Verstegen

Roest

et al. 2022

Cellular and Molecular Gastroenterology and Hepatology

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Background & Aims Liver and bile duct diseases often are associated with extensive cell death of cholangiocytes. Necroptosis represents a common mode of programmed cell death in cholangiopathy, however, detailed mechanistic knowledge is limited owing to the lack of appropriate in vitro models. To address this void, we investigated whether human intrahepatic cholangiocyte organoids (ICOs) can recapitulate cholangiopathy-associated necroptosis and whether this model can be used for drug screening. Methods We evaluated the clinical relevance of necroptosis in end-stage liver diseases and liver transplantation by immunohistochemistry. Cholangiopathy-associated programmed cell death was evoked in ICOs derived from healthy donors or patients with primary sclerosing cholangitis or alcoholic liver diseases by the various stimuli. Results The expression of key necroptosis mediators, receptor-interacting protein 3 and phosphorylated mixed lineage kinase domain-like, in cholangiocytes during end-stage liver diseases was confirmed. The phosphorylated mixed lineage kinase domain-like expression was etiology-dependent. Gene expression analysis confirmed that primary cholangiocytes are more prone to necroptosis compared with primary hepatocytes. Both apoptosis and necroptosis could be specifically evoked using tumor necrosis factor α and second mitochondrial-derived activator of caspases mimetic, with or without caspase inhibition in healthy and patient-derived ICOs. Necroptosis also was induced by ethanol metabolites or human bile in ICOs from donors and patients. The organoid cultures further uncovered interdonor variable and species-specific drug responses. Dabrafenib was identified as a potent necroptosis inhibitor and showed a protective effect against ethanol metabolite toxicity. Conclusions Human ICOs recapitulate cholangiopathy-associated necroptosis and represent a useful in vitro platform for the study of biliary cytotoxicity and preclinical drug evaluation.

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Section: Resultsmentioning

confidence: 99%

Recapitulating Cholangiopathy-Associated Necroptotic Cell Death In Vitro Using Human Cholangiocyte Organoids

Shi

Verstegen

Roest

et al. 2022

Cellular and Molecular Gastroenterology and Hepatology

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“…To determine whether the activation of pMLKL is involved in rat hepatic IRI, rat liver biopsies were collected after 22 hours of cold storage and 24 hours of reperfusion or sham operation ( Figure 1A ), followed by immunohistochemistry staining of pMLKL using a validated antibody ( 27 , 40 , 41 ). Compared to sham-operated rats, a significant increase of serum ALT (1153.0 (441.5-1652.0) vs 10.0 (10.0-17.5), p =0.029) and AST (1294.0 (654.5-1497.0) vs 66.5 (47.0-94.0), p =0.029) levels was observed in rats after LT ( Figure 1B ).…”

Section: Resultsmentioning

confidence: 99%

Liver Ischemia and Reperfusion Induce Periportal Expression of Necroptosis Executor pMLKL Which Is Associated With Early Allograft Dysfunction After Transplantation

et al. 2022

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BackgroundEarly allograft dysfunction (EAD) following liver transplantation (LT) remains a major threat to the survival of liver grafts and recipients. In animal models, it is shown that hepatic ischemia-reperfusion injury (IRI) triggers phosphorylation of Mixed Lineage Kinase domain-like protein (pMLKL) inducing necroptotic cell death. However, the clinical implication of pMLKL-mediated cell death in human hepatic IRI remains largely unexplored. In this study, we aimed to investigate the expression of pMLKL in human liver grafts and its association with EAD after LT.MethodsThe expression of pMLKL was determined by immunohistochemistry in liver biopsies obtained from both human and rat LT. Human liver biopsies were obtained at the end of preservation (T0) and ~1 hour after reperfusion (T1). The positivity of pMLKL was quantified electronically and compared in rat and human livers and post-LT outcomes. Multiplex immunofluorescence staining was performed to characterize the pMLKL-expressing cells.ResultsIn the rat LT model, significant pMLKL expression was observed in livers after IRI as compared to livers of sham-operation animals. Similarly, the pMLKL score was highest after IRI in human liver grafts (in T1 biopsies). Both in rats and humans, the pMLKL expression is mostly observed in the portal triads. In grafts who developed EAD after LT (n=24), the pMLKL score at T1 was significantly higher as compared to non-EAD grafts (n=40). ROC curve revealed a high predictive value of pMLKL score at T1 (AUC 0.70) and the ratio of pMLKL score at T1 and T0 (pMLKL-index, AUC 0.82) for EAD. Liver grafts with a high pMLKL index (>1.64) had significantly higher levels of serum ALT, AST, and LDH 24 hours after LT compared to grafts with a low pMLKL index. Multivariate logistical regression analysis identified the pMLKL-index (Odds ratio=1.3, 95% CI 1.1-1.7) as a predictor of EAD development. Immunohistochemistry on serial sections and multiplex staining identified the periportal pMLKL-positive cells as portal fibroblasts, fibrocytes, and a minority of cholangiocytes.ConclusionPeriportal pMLKL expression increased significantly after IRI in both rat and human LT. The histological score of pMLKL is predictive of post-transplant EAD and is associated with early liver injury after LT. Periportal non-parenchymal cells (i.e. fibroblasts) appear most susceptible to pMLKL-mediated cell death during hepatic IRI.

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“…Necroptosis affects nearly 40% of cells during pancreatitis; however, RIP3 deletion or treatment with necrostatin can improve pancreatitis . In caerulein-induced AP, deficiency of MLKL or RIP3 exerts a protective role by inhibiting necroptosis in acinar cells. , The induction of RIPK3-dependent necroptosis pathway in acinar cells by serum amyloid A3 leads to AP development . Additionally, Damaged acinar cells in pancreatitis are also characterized by pyroptosis.…”

Section: Discussionmentioning

confidence: 99%

PRMT7-Dependent Transcriptional Activation of Hmgb2 Aggravates Severe Acute Pancreatitis by Promoting Acsl1-Induced Ferroptosis

Su,

Chen,

Han

et al. 2024

J. Proteome Res.

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Severe acute pancreatitis (SAP) is a highly fatal abdominal emergency, and its association with protein arginine methyltransferase 7 (PRMT7), the sole known type III enzyme responsible for the monomethylation of arginine residue, remains unexplored. In this study, we observe an increase in the PRMT7 levels in the pancreas of SAP mice and Cerulein-LPS-stimulated AR42J cells. Overexpression of Prmt7 exacerbated pancreatic damage in SAP, while the inhibition of PRMT7 improved SAP-induced pancreatic damage. Furthermore, PRMT7 overexpression promoted inflammation, oxidative stress, and ferroptosis during SAP. Mechanically, PRMT7 catalyzed monomethylation at histone H4 arginine 3 (H4R3me1) at the promoter region of high mobility group proteins 2 (HMGB2), thereby enhancing its transcriptional activity. Subsequently, HMGB2 facilitated Acyl CoA synthase long-chain family member 1 (ACSL1) transcription by binding to its promoter region, resulting in the activation of ferroptosis. Inhibition of PRMT7 effectively alleviated ferroptosis in Cerulein-LPS-induced AR42J cells by suppressing the HMGB2-ACSL1 pathway. Overall, our study reveals that PRMT7 plays a crucial role in promoting SAP through its regulation of the HMGB2-ACSL1 pathway to accelerate ferroptosis.

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Serum amyloid A3 is required for caerulein‐induced acute pancreatitis through induction of RIP3‐dependent necroptosis

Cited by 9 publications

References 48 publications

Recapitulating Cholangiopathy-Associated Necroptotic Cell Death In Vitro Using Human Cholangiocyte Organoids

Recapitulating Cholangiopathy-Associated Necroptotic Cell Death In Vitro Using Human Cholangiocyte Organoids

Liver Ischemia and Reperfusion Induce Periportal Expression of Necroptosis Executor pMLKL Which Is Associated With Early Allograft Dysfunction After Transplantation

PRMT7-Dependent Transcriptional Activation of Hmgb2 Aggravates Severe Acute Pancreatitis by Promoting Acsl1-Induced Ferroptosis

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