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Updated: Aug 6, 2026
Preparing a Mice Model of Severe Acute Pancreatitis via a Combination of Caerulein and Lipopolysaccharide Intraperitoneal Injection
Published on: May 10, 2024
Trypsinogen-activated macrophage exosomes enriched in Rap1a exacerbate inflammation and predict severity in acute
Shengjie Dai1, Junru Wang1, Meilin Yi2
1Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, 325000, China.
Background:
Acute pancreatitis (AP) lacks reliable early biomarkers for predicting progression to severe acute pancreatitis (SAP). While macrophages are central to AP pathogenesis, the specific functional role of trypsinogen-activated macrophage-derived exosomes (Mφ-EXOs) remains inadequately defined. This study investigates whether these Mφ-EXOs and their cargo proteins propagate the inflammatory cascade and serve as early diagnostic assessor for AP severity.
Methods:
Macrophages were stimulated with trypsinogen in vitro, and the derived exosomes were isolated and characterized. Macrophage polarization and cytokine secretion profiles were evaluated following exosome treatment. Label-free quantitative proteomics was utilized to identify differentially expressed exosomal proteins. In vivo effects were validated using a cerulein-induced murine AP model. Clinically, plasma exosomal Rap1a levels were quantified for assessing AP severity, and diagnostic performance was assessed via receiver operating characteristic (ROC) analysis.
Results:
Macrophage internalization of trypsinogen induced a pro-inflammatory M1 phenotype. Trypsinogen-activated Mφ-EXOs promoted M1 polarization and enhanced IL-1β and TNF-α secretion in recipient macrophages. Proteomics identified Rap1a as significantly upregulated in these exosomes; its knockdown attenuated exosome-mediated M1 polarization. In vivo, administration of these exosomes exacerbated pancreatic and pulmonary injury. Clinically, plasma exosomal Rap1a was markedly elevated in SAP patients compared to those with non-severe AP. A predictive model combining exosomal Rap1a with serum calcium, white blood cell count, and IL-1β demonstrated high diagnostic accuracy.
Conclusions:
Trypsinogen-activated macrophages contribute to systemic inflammation in AP via the release of Rap1a-enriched exosomes. Plasma exosomal Rap1a demonstrates potential clinical utility as an early, mechanistically-grounded biomarker for predicting SAP severity.
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