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bioRxiv · 10.1101/2025.08.05.668601

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

Wang, L. D.·Dalan, R.·Hou, H. W.·Wong, S. L.
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Abstract

Neutrophils release their chromatin with toxic granular proteins as neutrophil extracellular traps (NETs) when activated. Diabetes exacerbates NET formation (NETosis), resulting in tissue damage and diabetic complications such as non-healing wounds. How diabetes predisposes neutrophils to NETosis remains unclear. Herein, we found that pharmacological inhibition or siRNA-knockdown of sirtuin 1 (SIRT1) increased NETosis in neutrophils of healthy humans and mice, unveiling SIRT1 as an endogenous suppressor of NETosis. In contrast, SIRT1 inhibition did not cause further increase in NETosis in neutrophils of diabetic patients and mice, indicative of SIRT1 dysfunction in disease state. Indeed, SIRT1 activity was significantly lower in neutrophils of diabetic individuals, accompanied by a concomitant increase in the activity of peptidylarginine deiminase 4 (PAD4), a key enzyme that mediates NETosis. PAD4 was co-detected with SIRT1 immunoprecipitated from HL-60-derived neutrophils cultured in basal glucose; such co- immunoprecipitation was absent in cells with high-glucose exposure, suggesting that hyperglycemia disrupts the SIRT1-PAD4 interaction. SIRT1 activators restored the SIRT1-PAD4 interaction and normalized the exacerbated NETosis and PAD4 activity in diabetes and hyperglycemia. This study reveals a novel regulatory role of SIRT1 on PAD4 activity. Revitalizing SIRT1 can be a new preventive or therapeutic strategy for combating NET-mediated inflammation in diabetes and beyond.

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Wang, L. D., Dalan, R., Hou, H. W., Wong, S. L.. 2025-08-05. Sirtuin 1 is an endogenous NETosis inhibitor that becomes dysfunctional in diabetes. https://doi.org/10.1101/2025.08.05.668601

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