• Am. J. Respir. Crit. Care Med. · Sep 2017

    Autophagy Primes Neutrophils for Neutrophil Extracellular Trap Formation During Sepsis.

    • So Young Park, Sanjeeb Shrestha, Young-Jin Youn, Jun-Kyu Kim, Shin-Yeong Kim, Kim Hyun Jung HJ 4 Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea., So-Hee Park, Won-Gyun Ahn, Shin Kim, Myung Goo Lee, Ki-Suck Jung, Yong Bum Park, Eun-Kyung Mo, Yousang Ko, Suh-Young Lee, Younsuck Koh, Myung Jae Park, Dong-Keun Song, and Chang-Won Hong.
    • 1 Department of Pulmonary and Critical Care Medicine, KyungHee University Medical Center, Seoul, Republic of Korea.
    • Am. J. Respir. Crit. Care Med. 2017 Sep 1; 196 (5): 577-589.

    RationaleNeutrophils are key effectors in the host's immune response to sepsis. Excessive stimulation or dysregulated neutrophil functions are believed to be responsible for sepsis pathogenesis. However, the mechanisms regulating functional plasticity of neutrophils during sepsis have not been fully determined.ObjectivesWe investigated the role of autophagy in neutrophil functions during sepsis in patients with community-acquired pneumonia.MethodsNeutrophils were isolated from patients with sepsis and stimulated with phorbol 12-myristate 13-acetate (PMA). The levels of reactive oxygen species 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 ResultsNeutrophils 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 NET formation and vice versa. In a mouse model of sepsis, the augmentation of autophagy improved survival via a NET-dependent mechanism.ConclusionsThese 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.

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