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Research, 23 Apr 2024 | https://doi.org/10.34133/research.0365 Diabetes Primes Neutrophils for Neutrophil Extracellular Trap Formation through Trained Immunity

Sanjeeb Shrestha^1†, Yu-Bin Lee^1†, Hoyul Lee^2,3, Yeon-Kyung Choi⁴, Bo-Yoon Park³, Mi-Jin Kim³, Young-Jin Youn¹, Sun-Hwa Kim¹, Soo-Jung Jung¹, Dong-Keun Song⁵, Hee Kyung Jin^6,7, Jae-Sung Bae^1,7, In-Kyu Lee^2,4,8, Jae-Han Jeon^2,3,4*, and Chang-Won Hong^1*

¹Department of Physiology, School of Medicine, Kyungpook National University, Daegu 41944, Republic of Korea.

²Leading-edge Research Center for Drug Discovery and Development for Diabetes and Metabolic Disease, Kyungpook National University Hospital, Daegu 41404, Republic of Korea. 3Research Institute of Aging and Metabolism, Kyungpook National University, Daegu 41404, Republic of Korea.

⁴Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu 41404, Republic of Korea.

⁵Department of Pharmacology, College of Medicine, Hallym University, Chuncheon 24252, Republic of Korea.

⁶Department of Laboratory Animal Medicine, College of Veterinary Medicine, Kyungpook National University, Daegu 41566, Republic of Korea.

⁷KNU Alzheimer’s disease Research Institute, Kyungpook National University, Daegu 41566, Republic of Korea.

⁸Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu 41940, Republic of Korea.

^*Address correspondence to: C.-W.H.; J.-H.J.

^†These author contributed equally to this work.

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.

논문정보

형식Research article
게재일2024년 04월 (BRIC 등록일 2024-04-25)
연구진국내 연구진
분야 의약학 > 응용의학

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