Polyethylene glycol loxenatide reduced neutrophil hyperactivation and signals in Behcet's disease models without provoking pyroptosis.
Evidence
Preclinical and ex vivo experiments tested PEX168 in neutrophils from Behcet's disease patients, LPS-stimulated healthy-donor neutrophils, and a murine Behcet's disease model using , NETosis, inflammasome, tissue, and ultrastructure assays.
Caveat
The evidence is limited to patient-derived cells, stimulated donor cells, and mice, with biphasic low-dose IL-1beta secretion and no human clinical treatment outcomes.
Simplified
BACKGROUND: Neutrophil hyperactivation, particularly through the release of neutrophil extracellular traps (), plays a crucial role in driving vascular inflammation in Behçet's disease (BD). While pyroptosis has been linked to the pathogenesis of BD, the effects of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on neutrophil dysregulation have not been previously explored.
METHODS: We investigated the effects of polyethylene glycol loxenatide (PEX168) on neutrophil activation using neutrophils isolated from BD patients, LPS-stimulated neutrophils from healthy donors, and a murine model of BD. We employed a variety of techniques, including western blotting, flow cytometry for reactive oxygen species () detection, immunohistochemistry on oral mucosa, colon, and pericardial vessels, transmission electron microscopy for cellular ultrastructure, and immunofluorescence to evaluate NETosis, pyroptosis, and inflammasome activation.
RESULTS: PEX168 significantly and dose-dependently reduced neutrophil hyperactivation, decreasing NETosis markers (CitH3, NE, MPO) and ROS. It preserved cellular ultrastructure by mitigating mitochondrial swelling and chromatin margination. While higher concentrations inhibited the NLRP3-caspase-1-IL-1β pathway, PEX168 did not induce pyroptosis, as uncleaved GSDMD-N' remained nuclear. Low concentrations transiently enhanced IL-1β secretion, indicating biphasic immunomodulation via NF-κB.
CONCLUSION: PEX168 attenuates neutrophil hyperactivation and NETosis in Behçet's disease via ROS suppression and upstream inflammasome regulation, disrupting inflammatory signaling without provoking pyroptosis. These findings support GLP-1 RAs as a targeted treatment for neutrophil-driven autoimmune disorders.
Key numbers
6.4 ng/mL
Decrease in Markers
treatment significantly lowered , , and levels.
8 μg/kg
Reduction in Levels
treatment led to notable reductions in oxidative stress.
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