Autophagy primes neutrophils for neutrophil extracellular trap formation during sepsis

So Young Park, Sanjeeb Shrestha, Young Jin Youn, Jun Kyu Kim, Shin Yeong Kim, Hyun Jung Kim, 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, Chang Won Hong

Research output: Contribution to journalArticlepeer-review

89 Scopus citations

Abstract

Rationale: Neutrophils 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. Objectives: We investigated the role of autophagy in neutrophil functions during sepsis in patients with community-acquired pneumonia. Methods: Neutrophils 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 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 NET 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.

Original languageEnglish
Pages (from-to)577-589
Number of pages13
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume196
Issue number5
DOIs
StatePublished - 1 Sep 2017

Keywords

  • Autophagy
  • Neutrophil
  • Neutrophil extracellular trap
  • Sepsis

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