2. Academic Validation
  3. Diabetes Primes Neutrophils for Neutrophil Extracellular Trap Formation through Trained Immunity

Diabetes Primes Neutrophils for Neutrophil Extracellular Trap Formation through Trained Immunity

  • Research (Wash D C). 2024 Apr 23:7:0365. doi: 10.34133/research.0365.
Sanjeeb Shrestha 1,  Yu-Bin Lee 1,  Hoyul Lee 2 3,  Yeon-Kyung Choi 4,  Bo-Yoon Park 3,  Mi-Jin Kim 3,  Young-Jin Youn 1,  Sun-Hwa Kim 1,  Soo-Jung Jung 1,  Dong-Keun Song 5,  Hee Kyung Jin 6 7,  Jae-Sung Bae 1 7,  In-Kyu Lee 2 4 8,  Jae-Han Jeon 2 3 4,  Chang-Won Hong 1
Affiliations

Affiliations

  • 1 Department of Physiology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea.
  • 2 Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu 41404, Republic of Korea.
  • 3 Research Institute of Aging and Metabolism, Kyungpook National University, Daegu 41404, Republic of Korea.
  • 4 Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu 41404, Republic of Korea.
  • 5 Department of Pharmacology, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea.
  • 6 Department of Laboratory Animal Medicine, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, Republic of Korea.
  • 7 KNU Alzheimer's disease Research Institute, Kyungpook National University, Daegu 41566, Republic of Korea.
  • 8 Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41940, Republic of Korea.
PMID: 38654733 DOI: 10.34133/research.0365
Abstract

Neutrophils are primed for neutrophil extracellular trap (NET) formation during diabetes, and excessive NET formation from primed neutrophils compromises wound healing in patients with diabetes. Here, we demonstrate that trained immunity mediates diabetes-induced NET priming in neutrophils. Under diabetic conditions, neutrophils exhibit robust metabolic reprogramming comprising enhanced glycolysis via the pentose phosphate pathway and fatty acid oxidation, which result in the accumulation of acetyl-coenzyme A. Adenosine 5'-triphosphate-citrate lyase-mediated accumulation of acetyl-coenzyme A and histone acetyltransferases further induce the acetylation of lysine residues on histone 3 (AcH3K9, AcH3K14, and AcH3K27) and histone 4 (AcH4K8). The pharmacological inhibition of adenosine 5'-triphosphate-citrate lyase and histone acetyltransferases completely inhibited high-glucose-induced NET priming. The trained immunity of neutrophils was further confirmed in neutrophils isolated from patients with diabetes. Our findings suggest that trained immunity mediates functional changes in neutrophils in diabetic environments, and targeting neutrophil-trained immunity may be a potential therapeutic target for controlling inflammatory complications of diabetes.

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