So Young Park1,*, Sanjeeb Shrestha2,*, Young-Jin Youn2, Jun-Kyu Kim3, Shin-Yeong Kim2, Hyun Jung Kim4, So-Hee Park5, Won-Gyun Ahn2, Shin Kim6, Myung Goo Lee7,8, Ki-Suck Jung7,9, Yong Bum Park7,10, Eun-Kyung Mo7,10, Yousang Ko7,10, Suh-Young Lee7,8, Younsuck Koh11, Myung Jae Park1, Dong-Keun Song2, Chang-Won Hong3,†
1Department of Pulmonary and Critical Care Medicine, KyungHee University Medical Center, Seoul, 20447, Republic of Korea.
2Department of Pharmacology, College of Medicine, Hallym University, Chuncheon, 24252, Republic of Korea.
3Department of Physiology, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea.
4Department of Internal Medicine, Kyungpook National University Hospital, Daegu, 41944, Republic of Korea.
5Department of Pulmonary and Critical Care Medicine, KyungHee University Hospital at Gangdong, Seoul,05278, Republic of Korea
6Department of Immunology, Keimyung University School of Medicine, Daegu, 42601, Republic of Korea.
7Lung Research Institute of Hallym University, College of Medicine, Hallym University, Seoul, 05355, Republic of Korea.
8Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal
Medicine, Chuncheon Sacred Heart Hospital, Chuncheon, 24252, Republic of Korea.
9Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal
Medicine, Hallym University Sacred Heart Hospital, Anyang, 14068, Republic of Korea.
10Division of Pulmonary, Allergy and Critical Care Medicine, Department of Internal
Medicine, Kangdong Sacred Heart Hospital, Seoul, 05355, Republic of Korea.
11Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
*These authors contributed equally to this work.
†Correspondence to : Chang-Won Hong, M.D., Ph.D.
Department of Physiology, School of Medicine, Kyungpook National University 680 Gukchaeborang-ro, Daegu 41944, Republic of Korea
Rationale: Neutrophils are key effectors in the host's immune response to sepsis. Excessive stimulation or dysregulated neutrophil functions are thought to be responsible for sepsis pathogenesis. However, the mechanisms regulating functional plasticity of neutrophils during sepsis have not been fully determined. Objectives: We investigated the role of autophagy in neutrophil functions during sepsis in patients with community-acquired pneumonia. Methods: Neutrophils were isolated from septic patients, and stimulated with phorbol 12-myristate 13-acetate (PMA). The levels of reactive oxygen species (ROS) generation, neutrophil extracellular trap (NET) formation, and granule release, and the autophagic status were evaluated. The effect of neutrophil autophagy augmentation was further evaluated in a mouse model of sepsis. Measurements and Main Results: Neutrophils isolated from patients who survived sepsis showed an increase in autophagy induction, and were primed for NET formation in response to subsequent PMA stimulation. In contrast, neutrophils isolated from patients who did not survive sepsis showed dysregulated autophagy and a decreased response to PMA stimulation. The induction of autophagy primed healthy neutrophils for NETs formation and vice versa. In a mouse model of sepsis, the augmentation of autophagy improved survival via a NET-dependent mechanism. Conclusions: These results indicate that neutrophil autophagy primes neutrophils for increased NET formation, which is important for proper neutrophil effector functions during sepsis. Our study provides important insights into the role of autophagy in neutrophils during sepsis.
Keywords: Neutrophil, Autophagy, Sepsis, Neutrophil extracellular trap