Sirtuin 1 is an endogenous NETosis inhibitor that becomes dysfunctional in diabetes.
Level 5 - mechanism / opinion, no new human data
Preclinical bench and animal study using human/mouse neutrophils and cell culture models.
PubMed 41549423 · doi:10.1093/jleuko/qiag006
What was done
Researchers evaluated the role of sirtuin 1 (SIRT1) in neutrophil extracellular trap formation (NETosis) using neutrophils isolated from healthy and diabetic humans and mice, alongside HL-60-derived neutrophils (dHL-60). They performed pharmacological inhibition and siRNA knockdown of SIRT1, measured SIRT1 deacetylase and peptidylarginine deiminase 4 (PAD4) activity, assessed SIRT1-PAD4 binding via co-immunoprecipitation under basal and high-glucose conditions, and tested the effects of SIRT1 activators on NETosis and diabetic wound healing.
What was found
Inhibition or knockdown of SIRT1 increased NETosis in healthy human and mouse neutrophils, but caused no further increase in diabetic neutrophils. SIRT1 deacetylase activity was lower and PAD4 activity was higher in diabetic neutrophils. PAD4 co-immunoprecipitated with SIRT1 in healthy human neutrophils and basal-glucose dHL-60 cells, but this interaction was absent in diabetic neutrophils and high-glucose dHL-60 cells. Treatment with SIRT1 activators restored the SIRT1-PAD4 interaction, normalized PAD4 activity and NETosis, and improved diabetic wound healing. The abstract reports no numerical values or effect sizes.
Why it matters
These findings establish SIRT1 as an endogenous suppressor of NETosis and identify the disruption of the SIRT1-PAD4 complex as a mechanism underlying exaggerated NET formation in diabetes. Activating SIRT1 offers a potential therapeutic target to reduce NET-mediated tissue injury and improve diabetic wound healing.
Limits
The study is based on preclinical cell and animal models. The abstract provides no exact sample sizes, donor demographics, quantitative effect sizes, or statistical confidence intervals, and clinical efficacy in humans has not yet been established.
Cited by
- supports Sugar spikes suppress sirtuin enzyme activity.