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Updated: Nov 2, 2025
Preparing a Mice Model of Severe Acute Pancreatitis via a Combination of Caerulein and Lipopolysaccharide Intraperitoneal Injection
Published on: May 10, 2024
Necroptosis protects against exacerbation of acute pancreatitis
Michittra Boonchan1, Hideki Arimochi1, Kunihiro Otsuka1,2
1Department of Immunology and Parasitology, Graduate School of Medicine, Tokushima University, Tokushima, Japan.
Abstract:
The sensing of various extrinsic stimuli triggers the receptor-interacting protein kinase-3 (RIPK3)-mediated signaling pathway, which leads to mixed-lineage kinase-like (MLKL) phosphorylation followed by necroptosis. Although necroptosis is a form of cell death and is involved in inflammatory conditions, the roles of necroptosis in acute pancreatitis (AP) remain unclear. In the current study, we administered caerulein to Ripk3- or Mlkl-deficient mice (Ripk3-/- or Mlkl-/- mice, respectively) and assessed the roles of necroptosis in AP. We found that Ripk3-/- mice had significantly more severe pancreatic edema and inflammation associated with macrophage and neutrophil infiltration than control mice. Consistently, Mlkl-/- mice were more susceptible to caerulein-induced AP, which occurred in a time- and dose-dependent manner, than control mice. Mlkl-/- mice exhibit weight loss, edematous pancreatitis, necrotizing pancreatitis, and acinar cell dedifferentiation in response to tissue damage. Genetic deletion of Mlkl resulted in downregulation of the antiapoptotic genes Bclxl and Cflar in association with increases in the numbers of apoptotic cells, as detected by TUNEL assay. These findings suggest that RIPK3 and MLKL-mediated necroptosis exerts protective effects in AP and caution against the use of necroptosis inhibitors for AP treatment.
Insights
Receptor-interacting protein kinase-3 (RIPK3) and mixed-lineage kinase-like (MLKL) mediated necroptosis protect against acute pancreatitis (AP). Genetic deficiency of RIPK3 or MLKL worsens AP severity, suggesting necroptosis is protective.
Area of Science:
- Cellular Biology
- Immunology
- Pathology
Background:
- Necroptosis, a programmed form of necrosis, is triggered by receptor-interacting protein kinase-3 (RIPK3) and mediated by mixed-lineage kinase-like (MLKL).
- While necroptosis is implicated in inflammation, its specific role in acute pancreatitis (AP) pathogenesis is not well understood.
Purpose of the Study:
- To investigate the role of RIPK3- and MLKL-mediated necroptosis in the context of acute pancreatitis.
- To determine the therapeutic implications of targeting necroptosis in AP.
Main Methods:
- Utilized caerulein-induced acute pancreatitis model in Ripk3-deficient (Ripk3-/-) and Mlkl-deficient (Mlkl-/-) mice.
- Assessed severity of pancreatitis, including edema, inflammation, immune cell infiltration, weight loss, and acinar cell dedifferentiation.
- Quantified apoptosis using TUNEL assay and analyzed expression of antiapoptotic genes (Bclxl, Cflar).
Main Results:
- Ripk3-/- mice exhibited exacerbated pancreatic edema and inflammation with increased macrophage and neutrophil infiltration compared to controls.
- Mlkl-/- mice showed increased susceptibility to caerulein-induced AP, manifesting as weight loss, severe pancreatitis, and acinar cell dedifferentiation.
- MLKL deficiency led to decreased expression of antiapoptotic genes Bclxl and Cflar, correlating with increased apoptotic cell numbers.
Conclusions:
- RIPK3 and MLKL-mediated necroptosis play a protective role in acute pancreatitis.
- Targeting necroptosis pathways may not be beneficial and could potentially be detrimental for AP treatment.
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