Gasdermin E deficiency ameliorates caerulein/lipopolysaccharide -induced severe acute pancreatitis and systemic inflammation in mice.

Abstract

This study investigated whether gasdermin E (GSDME) deficiency attenuates caerulein/lipopolysaccharide (LPS)-induced severe acute pancreatitis (SAP) in mice. Wild-type (WT) and Gsdme-knockout (KO) mice were assigned to PBS or caerulein/LPS groups. SAP was induced by repeated intraperitoneal caerulein injections for 2 consecutive days followed by a single LPS injection. Pancreatic injury was assessed by body weight change, pancreas-to-body weight ratio, serum amylase and lipase, and histopathology. Inflammatory responses were evaluated by serum cytokines, serum and pancreatic IL-33, HMGB1 subcellular distribution, and MPO/F4/80 immunohistochemistry. Cell death and gasdermin pathway activation were assessed by TUNEL staining and Western blotting. Compared with WT mice subjected to caerulein/LPS challenge, Gsdme-deficient mice showed less body weight loss, lower histopathological scores, and attenuated systemic inflammatory responses. Serum and pancreatic IL-33 levels, HMGB1 nuclear-to-cytoplasmic translocation, and circulating HMGB1 were also reduced in KO mice. Consistently, pancreatic MPO- and F4/80-positive inflammatory cell infiltration, TUNEL positivity, and the cleaved caspase-3/total caspase-3 ratio were reduced in KO mice. Cleaved and full-length GSDME were absent in KO pancreatic tissues, whereas caerulein/LPS treatment increased cleaved GSDME levels in WT mice. The cleaved caspase-1/total caspase-1 ratio and cleaved GSDMD expression increased after caerulein/LPS challenge in both genotypes, but neither was further elevated in KO mice, indicating no detectable compensatory upregulation of the canonical caspase-1/GSDMD pathway at the examined time point. Collectively, Gsdme deficiency alleviated caerulein/LPS-induced pancreatic injury and systemic inflammation, indicating that the caspase-3/GSDME axis contributes importantly, but not exclusively, to experimental SAP.