Peptidylarginine deiminase 4-mediated neutrophil extracellular trap formation aggravates β-cell damage in type 1 diabetes: A multi-model study.

Abstract

AIMS: Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by progressive destruction of pancreatic β cells. Increasing evidence suggests that neutrophils and neutrophil extracellular traps (NETs) may contribute to early islet inflammation; however, their precise role in T1DM pathogenesis remains incompletely understood. This study aimed to investigate the involvement of neutrophils and NET formation in the development and progression of T1DM and to explore their potential immunopathological significance. MATERIALS AND METHODS: Relevant clinical samples from patients with newly diagnosed T1DM and appropriate controls were analyzed, together with experimental data derived from established animal models of T1DM. Neutrophil activation and NET formation were assessed using established biomarkers, including citrullinated histone H3 and myeloperoxidase-DNA complexes. Inflammatory responses and pancreatic islet injury were evaluated using immunological, histological, and molecular approaches. RESULTS: Elevated levels of circulating NET-associated markers were observed in patients with newly diagnosed T1DM and in early-stage diabetic animal models. Neutrophil infiltration into pancreatic islets was evident at early disease stages and was associated with increased inflammatory activity and β-cell dysfunction. Excessive NET formation correlated with enhanced immune activation, suggesting a contributory role of neutrophils and NETs in amplifying islet inflammation and autoimmune responses. CONCLUSIONS: These findings indicate that neutrophils and NETs participate in the early immunopathogenesis of T1DM and may promote β-cell injury through inflammatory and immune-mediated mechanisms. Targeting dysregulated neutrophil activation and NET formation may represent a potential therapeutic strategy for preserving β-cell function and modifying disease progression in T1DM.