Macrophage Extracellular Traps Modulate the Compensatory Anti-inflammatory Response Syndrome through IL-33/ST2 Signaling in Severe Acute Pancreatitis

作者：Quan Zhou, Zhao Shi, Xuan Wang, Lingxi Meng, Kun Liu, Siqi Zhou, Yihang Jiang, Shuang Nie, Yuanyuan Yu, Hao Zhu, Mingdong Liu, Bo Kong, Helmut Friess, Lei Wang, Hongzhen Li, Shanshan Shen, Xiaoping Zou · 发表于：International Journal of Biological Sciences · 年份：2025 · DOI：10.7150/ijbs.116740 · 被引用次数：7 · 研究领域：Pancreatitis Pathology and Treatment、Eosinophilic Esophagitis

Severe acute pancreatitis (SAP) is characterized by biphasic systemic inflammation, progressing from initial pro-inflammatory systemic inflammatory response syndrome (SIRS) to subsequent immunosuppressive compensatory anti-inflammatory response syndrome (CARS), which increases infection risks and predicts poor prognosis. Using a pancreatic duct ligation and caerulein-induced SAP murine model, we demonstrate that macrophage extracellular traps (METs) play a pivotal role in immune regulation. Mechanistically, acinar cell activation of the cGAS-STING pathway triggers pyroptosis-mediated IL-33 release. METs subsequently process IL-33 into highly bioactive isoforms through METs-derived proteases (including MMP-12), thereby initiating ST2 receptor-mediated type-2 immune responses. Clinical validation revealed elevated serum METs marker and IL-33 levels in SAP patients. Therapeutic interventions with DNase I and Cl-amidine significantly attenuated IL-33 release, Th2 cell activation, and disease severity in experimental models. Our findings establish METs as critical regulators of SAP-associated CARS and propose METs inhibition as a promising therapeutic strategy for SAP management.