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Updated: Mar 23, 2026
Preparing a Mice Model of Severe Acute Pancreatitis via a Combination of Caerulein and Lipopolysaccharide Intraperitoneal Injection
Published on: May 10, 2024
The Receptor for Advanced Glycation End Products Activates the AIM2 Inflammasome in Acute Pancreatitis
Rui Kang1, Ruochan Chen2, Min Xie3
1Department of Surgery, University of Pittsburgh, Pittsburgh, PA 15219; kangr@upmc.edu tangd2@upmc.edu zehh@upmc.edu.
Abstract:
Severe acute pancreatitis (AP) is responsible for significant human morbidity and mortality worldwide. Currently, no specific treatments for AP exist, primarily due to the lack of a mechanistic understanding of sterile inflammation and the resultant multisystem organ dysfunction, the pathologic response of AP linked to early death. In this study, we demonstrate that the class III major histocompatibility region III receptor for advanced glycation end products (RAGE) contributes to AP by modulating inflammasome activation in macrophages. RAGE mediated nucleosome-induced absent in melanoma 2 (but not NLRP3) inflammasome activation by modulating dsRNA-dependent protein kinase phosphorylation in macrophages. Pharmacological and genetic inhibition of the RAGE-dsRNA-dependent protein kinase pathway attenuated the release of inflammasome-dependent exosomal leaderless cytokines (e.g., IL-1β and high-mobility group box 1) in vitro. RAGE or absent in melanoma 2 depletion in mice limited tissue injury, reduced systemic inflammation, and protected against AP induced by l-arginine or cerulein in experimental animal models. These findings define a novel role for RAGE in the propagation of the innate immune response with activation of the nucleosome-mediated inflammasome and will help guide future development of therapeutic strategies to treat AP.
Insights
Severe acute pancreatitis (AP) involves sterile inflammation. This study reveals the receptor for advanced glycation end products (RAGE) drives AP by activating the absent in melanoma 2 inflammasome, offering new therapeutic targets.
Area of Science:
- Immunology
- Molecular Biology
- Pathology
Background:
- Severe acute pancreatitis (AP) causes significant global morbidity and mortality.
- Current AP treatments are limited by a poor understanding of sterile inflammation and organ dysfunction.
- A specific mechanism linking innate immune response to AP pathogenesis is needed.
Purpose of the Study:
- To investigate the role of the receptor for advanced glycation end products (RAGE) in AP pathogenesis.
- To elucidate the molecular pathways by which RAGE influences inflammasome activation in AP.
- To identify potential therapeutic targets for AP.
Main Methods:
- Investigated RAGE's role in inflammasome activation (AIM2, NLRP3) in macrophages.
- Examined the modulation of dsRNA-dependent protein kinase (PKR) phosphorylation by RAGE.
- Utilized pharmacological and genetic inhibition of the RAGE-PKR pathway in vitro and in vivo models of AP.
Main Results:
- RAGE mediates nucleosome-induced AIM2 inflammasome activation, independent of NLRP3.
- RAGE-PKR pathway inhibition reduced release of IL-1β and HMGB1 in vitro.
- RAGE or AIM2 depletion in mice protected against AP, reducing tissue injury and systemic inflammation.
Conclusions:
- RAGE plays a critical role in AP by promoting innate immune responses via AIM2 inflammasome activation.
- The RAGE-PKR pathway is a key mediator of sterile inflammation in AP.
- Targeting the RAGE-AIM2 axis presents a promising therapeutic strategy for AP.
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