Sirtuin 1 is an endogenous NETosis inhibitor that becomes dysfunctional in diabetes

Area of Science:

• Immunology
• Metabolic Disorders
• Molecular Biology

Background:

• Neutrophil extracellular traps (NETs) are released chromatin with toxic proteins during neutrophil activation.
• Diabetes mellitus exacerbates NET formation (NETosis), contributing to tissue damage and complications like non-healing wounds.
• The mechanisms underlying diabetes-induced NETosis remain largely unknown.

Purpose of the Study:

• To investigate the role of sirtuin 1 (SIRT1) in regulating NETosis, particularly in the context of diabetes.
• To elucidate the molecular interaction between SIRT1 and peptidylarginine deiminase 4 (PAD4) in NET formation.
• To explore the therapeutic potential of SIRT1 activation for diabetic complications.

Main Methods:

• Pharmacological inhibition and siRNA-knockdown of SIRT1 in neutrophils from healthy and diabetic humans and mice.
• Assessing NETosis levels and peptidylarginine deiminase 4 (PAD4) activity.
• Co-immunoprecipitation assays to examine the interaction between SIRT1 and PAD4 under varying glucose conditions.
• Treatment with SIRT1 activators in diabetic models.

Main Results:

• SIRT1 acts as an endogenous suppressor of NETosis; its inhibition increases NETosis in healthy neutrophils.
• SIRT1 activity and its interaction with PAD4 are diminished in neutrophils from diabetic individuals and under high glucose conditions.
• Hyperglycemia disrupts the SIRT1-PAD4 interaction, leading to increased PAD4 activity and NETosis.
• SIRT1 activators restored the SIRT1-PAD4 interaction, normalized NETosis and PAD4 activity, and improved wound healing in diabetic models.

Conclusions:

• SIRT1 plays a critical role in suppressing NETosis by interacting with and regulating PAD4 activity.
• Dysfunctional SIRT1 contributes to exacerbated NETosis in diabetes.
• Targeting SIRT1 offers a promising therapeutic strategy for managing NET-mediated inflammation and improving outcomes in diabetes.