Trypsinogen-activated macrophage exosomes enriched in Rap1a exacerbate inflammation and predict severity in acute pancreatitis.

Authors

Shengjie Dai, Junru Wang, Meilin Yi, Ebrahim Abdo, Haobing Li, Hongru Kong, Liqi Bao, Geer Chen, Hongwei Sun, Keqing Shi

Published in

Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.]. Jul 22, 2026. Epub Jul 22, 2026.

Abstract

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.
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.
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.
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.

PMID:
42498589
Bibliographic data and abstract were imported from PubMed on 25 Jul 2026.

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