| Summary: | When activated, neutrophils can unravel their chromatin and release it along with toxic granular proteins, forming neutrophil extracellular traps (NETs). Being highly pro-inflammatory, NETs are injurious to organs and tissues. In diabetes, formation of NETs (NETosis) is exacerbated, causing diabetic complications including diabetic retinopathy and delayed wound healing. How diabetes augments NETosis remains unclear. Herein, I report that sirtuin 1 (SIRT1) functions as an endogenous inhibitor of NETosis in healthy neutrophils. Reduction in SIRT1 activity in diabetes resulted in excessive NET formation, which could be normalized by SIRT1 activators. My work also defined the role of oxidized DNA and endoplasmic reticulum stress in the activation of neutrophil NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome in the generation of excessive NETs in diabetes. The findings have advanced our understanding of NETosis biology and laid an important foundation for the development of novel therapeutics for combating diabetic complications and beyond.
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