NET Proteome in Established Type 1 Diabetes Is Enriched in Metabolic Proteins

Area of Science:

• Immunology
• Metabolic Research
• Type 1 Diabetes Research

Background:

• Type 1 diabetes (T1D) involves autoimmune destruction of pancreatic beta cells.
• Neutrophil abnormalities and neutrophil extracellular trap (NET) formation (NETosis) are implicated in T1D.
• It remains unclear if these neutrophil changes are intrinsic defects or environmentally induced.

Purpose of the Study:

• To investigate the proteomic differences in NETs (NETome) from neutrophils of individuals with T1D compared to healthy controls (HC).
• To assess if NETosis and metabolic profiles differ between T1D and HC neutrophils.

Main Methods:

• Proteomic analysis of NETs from neutrophils stimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin.
• Comparison of NETosis levels, plasma cytokines, and NET markers between T1D and HC groups.
• Metabolic profiling, including extracellular acidification rate (glycolysis) and mitochondrial respiration.

Main Results:

• NETosis and plasma inflammatory markers were comparable between T1D and HC.
• The NETome of T1D neutrophils differed significantly from HC, enriched in metabolic pathway proteins.
• Neutrophil glycolysis and mitochondrial respiration were similar in both groups.

Conclusions:

• T1D neutrophils exhibit an altered NETome enriched in metabolic proteins, despite normal NETosis and bioenergetics.
• This distinct NETome may represent an adaptive mechanism in T1D neutrophils.
• This adaptation could help maintain innate immune defense and inflammation resolution functions.