Diabetes Primes Neutrophils for Neutrophil Extracellular Trap Formation through Trained Immunity

Area of Science:

• Immunology
• Metabolic Disease
• Cellular Biology

Background:

• Diabetes mellitus is associated with impaired wound healing.
• Neutrophils play a critical role in inflammation and immunity.
• Neutrophil extracellular traps (NETs) are implicated in various inflammatory conditions.

Purpose of the Study:

• To investigate the role of trained immunity in diabetes-induced neutrophil extracellular trap (NET) formation.
• To elucidate the metabolic and epigenetic mechanisms underlying NET priming in diabetic neutrophils.
• To explore potential therapeutic targets for managing diabetes-related inflammatory complications.

Main Methods:

• Analysis of neutrophil metabolic reprogramming under diabetic conditions (high glucose).
• Assessment of acetyl-coenzyme A accumulation and histone acetylation.
• Pharmacological inhibition of key enzymes (adenosine 5'-triphosphate-citrate lyase, histone acetyltransferases).
• Validation in neutrophils isolated from patients with diabetes.

Main Results:

• Diabetic conditions induce metabolic reprogramming in neutrophils, enhancing glycolysis and fatty acid oxidation.
• This reprogramming leads to acetyl-coenzyme A accumulation and subsequent histone acetylation.
• Inhibition of adenosine 5'-triphosphate-citrate lyase and histone acetyltransferases abrogated high-glucose-induced NET priming.
• Trained immunity was confirmed in neutrophils from diabetic patients, linking it to NET priming.

Conclusions:

• Trained immunity mediates diabetes-induced NET priming in neutrophils.
• Metabolic and epigenetic alterations are key mechanisms driving this phenomenon.
• Targeting neutrophil-trained immunity presents a potential therapeutic avenue for diabetic inflammatory complications.