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

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.